Alternative titles; symbols
HGNC Approved Gene Symbol: STK11
SNOMEDCT: 54411001; ICD10CM: Q85.89;
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:1,205,778-1,228,431 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Melanoma, malignant, somatic | 155600 | 3 | |
| Pancreatic cancer, somatic | 260350 | 3 | ||
| Peutz-Jeghers syndrome | 175200 | Autosomal dominant | 3 | |
| Testicular tumor, somatic | 273300 | 3 |
STK11 is a serine/threonine kinase that regulates energy metabolism and cell polarity (Xu et al., 2013).
Jenne et al. (1998) identified and characterized a novel human gene encoding the serine/threonine kinase STK11 within a region on chromosome 19p13.3 identified as a locus for Peutz-Jeghers syndrome (PJS; 175200) by Hemminki et al. (1997). A sequence similarity search in GenBank with the genomic sequence obtained from the telomeric end of a cosmid from the PJS region revealed identity of 32 bp with a coding region of a human serine/threonine protein kinase, previously named LKB1 but renamed STK11. To prove that STK11 was indeed located in this region, Jenne et al. (1998) selected primers from the 5-prime and 3-prime ends of the STK11 cDNA sequence for direct sequence analysis of the cosmid.
Smith et al. (1999) found that the mouse Lkb1 gene encodes a protein showing strong sequence similarity to human LKB1. The 3-prime end of Lkb1 in the mouse was found to lie in very close proximity to the 3-prime end of an apparently unrelated gene called R29144/1, and it seemed probable that overlapping transcripts of the 2 genes are produced. Using transfection of Lkb1 cDNAs, Smith et al. (1999) showed that Lkb1 is most likely a nuclear protein; furthermore, they defined a nuclear localization signal within the protein sequence. Smith et al. (1999) hypothesized that the defect in PJS may result directly in changes in gene expression in the nucleus of target cells.
Karuman et al. (2001) demonstrated that LKB1 physically associates with p53 (191170) and regulates specific p53-dependent apoptosis pathways. LKB1 protein is present in both the cytoplasm and nucleus of living cells and translocates to mitochondria during apoptosis. In vivo, LKB1 is highly upregulated in pyknotic intestinal epithelial cells. In contrast, polyps arising in PJS patients are devoid of LKB1 staining and have reduced numbers of apoptotic cells. The authors proposed that a deficiency in apoptosis is a key factor in the formation of multiple benign intestinal polyps in PJS patients, and possibly for the subsequent development of malignant tumors in these patients.
Smith et al. (2001) used a yeast 2-hybrid system to identify a novel leucine-rich repeat containing protein, which they called LIP1 (607172), that interacts with LKB1. The LIP1 gene encodes a cytoplasmic protein of 121 kD. When LKB1 and LIP1 were coexpressed in vitro, the proportion of cytoplasmic LKB1 dramatically increased, suggesting that LIP1 may regulate LKB1 function by controlling its subcellular localization. Ectopic expression of both LKB1 and LIP1 in Xenopus embryos induced a secondary body axis, resembling the effects of ectopic expression of TGF-beta (190180) superfamily members and their downstream effectors. Furthermore, LIP1 interacted with the TGF-beta-regulated transcription factor SMAD4 (600993), forming a LKB1-LIP1-SMAD4 ternary complex. Since SMAD4 mutations give rise to juvenile intestinal polyposis syndrome (PJI; 174900), the authors suggested that a mechanistic link may exist between PJI and PJS.
Restoring LKB1 activity into cancer cell lines defective for its expression results in a G1 cell cycle arrest. Tiainen et al. (2002) showed that reintroduced active LKB1 was cytoplasmic and nuclear, whereas most kinase-defective PJS mutants of LKB1 localized predominantly to the nucleus. Moreover, when LKB1 was forced to remain cytoplasmic through disruption of the nuclear localization signal, it retained full growth suppression activity in a kinase-dependent manner. LKB1-mediated G1 arrest was found to be bypassed by coexpression of the G1 cyclins cyclin D1 (168461) and cyclin E (123837). Protein levels of the CDK inhibitor p21 (116899) and p21 promoter activity were specifically upregulated in LKB1-transfected cells. Both the growth arrest and the induction of the p21 promoter were found to be p53 (191170)-dependent. The authors suggested that growth suppression by LKB1 is mediated through signaling of cytoplasmic LKB1 to induce p21 through a p53-dependent mechanism.
Martin and St Johnston (2003) demonstrated that Drosophila Lkb1 is required for the early anterior-posterior polarity of the oocyte, and for the repolarization of the oocyte cytoskeleton that defines the embryonic anterior-posterior axis. Lkb1 is phosphorylated by Par1 in vitro, and overexpression of Lkb1 partially rescues the Par1 phenotype. These 2 kinases, therefore, function in a conserved pathway for axis formation in flies and worms. Lkb1 mutant clones also disrupt apical-basal epithelial polarity, suggesting a general role in cell polarization. Martin and St Johnston (2003) showed that Drosophila Lkb1 is phosphorylated by protein kinase A (PKA; see 176911) at a conserved site that is important for its activity. Thus, Martin and St Johnston (2003) suggested that Drosophila and human LKB1 may be functional homologs, and that it may be the loss of cell polarity that contributes to tumor formation in individuals with PJS.
Baas et al. (2003) showed that endogenous LKB1 and STRAD (608626) form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners. STRAD determined the subcellular localization of wildtype, but not mutant, LKB1, translocating it from nucleus to cytoplasm. An LKB1 mutation identified in a family with Peutz-Jeghers syndrome (175200) that did not compromise LKB1 kinase activity interfered with LKB1 binding to STRAD, and hence with STRAD-dependent regulation. Removal of endogenous STRAD by small interfering RNA abrogated LKB1-induced G1 arrest.
Baas et al. (2004) constructed intestinal epithelial cell lines in which inducible STRAD activated LKB1. Upon LKB1 activation, single cells rapidly remodeled their actin cytoskeletons to form apical brush borders. The junctional proteins ZO1 (601009) and p120 (CTNND1; 601045) redistributed in a dotted circle peripheral to the brush border, in the absence of cell-cell contacts. Apical and basolateral markers sorted to their respective membrane domains. Baas et al. (2004) concluded that LKB1 can induce complete polarity in intestinal epithelial cells, which can fully polarize in the absence of junctional cell-cell contacts.
Mehenni et al. (2005) identified PTEN (601728) as an LKB1-interacting protein. Several LKB1 point mutations associated with PJS disrupted the interaction with PTEN, suggesting that loss of this interaction might contribute to PJS. Although PTEN and LKB1 are predominantly cytoplasmic and nuclear, respectively, their interaction led to a cytoplasmic relocalization of LKB1. PTEN was found to be a substrate of the kinase LKB1 in vitro. As PTEN is a dual phosphatase mutated in autosomal inherited disorders with phenotypes similar to those of PJS, such as Cowden syndrome (158350), Mehenni et al. (2005) suggested a functional link between the proteins involved in different hamartomatous polyposis syndromes and emphasized the central role played by LKB1 as a tumor suppressor in the small intestine.
Ji et al. (2007) used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumor suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 (191170) or Ink4a/Arf (also known as Cdkn2a, 600160), in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumors demonstrated shorter latency, an expanded histologic spectrum (adeno-, squamous, and large-cell carcinoma), and more frequent metastasis compared to tumors lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analyzed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumors identified a variety of metastasis-promoting genes, such as NEDD9 (602265), VEGFC (601528), and CD24 (600074), as targets of LKB1 repression in lung cancer. Ji et al. (2007) concluded that their studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation, and metastasis.
Katajisto et al. (2008) demonstrated that either monoallelic or biallelic loss of murine STK11 limited to transgelin (TAGLN; 600818)-expressing mesenchymal cells resulted in premature postnatal death as a result of gastrointestinal polyps indistinguishable from those in Peutz-Jeghers syndrome. STK11-deficient mesenchymal cells produced less TGF-beta (190180), and defective TGF-beta signaling to epithelial cells coincided with epithelial proliferation. Katajisto et al. (2008) also noted TGF-beta signaling defects in polyps of individuals with Peutz-Jeghers syndrome, suggesting that the identified stromal-derived mechanism of tumor suppression is also relevant in Peutz-Jeghers syndrome.
Nakada et al. (2010) found that deletion of the Lkb1 gene in mice caused increased hematopoietic stem cell (HSC) division, rapid HSC depletion, and pancytopenia. HSCs depended more acutely on Lkb1 for cell cycle regulation and survival than many other hematopoietic cells. HSC depletion did not depend on mammalian target of rapamycin (mTOR; 601231) activation or oxidative stress. Lkb1-deficient HSCs, but not myeloid progenitors, had reduced mitochondrial membrane potential and ATP levels. HSCs deficient for 2 catalytic alpha-subunits of AMP-activated protein kinase (AMPK; e.g., 602739) showed similar changes in mitochondrial function but remained able to reconstitute irradiated mice. Lkb1-deficient HSCs, but not AMPK-deficient HSCs, exhibited defects in centrosomes and mitotic spindles in culture, and became aneuploid. Nakada et al. (2010) concluded that Lkb1 is therefore required for HSC maintenance through AMPK-dependent and AMPK-independent mechanisms, revealing differences in metabolic and cell cycle regulation between HSCs and some other hematopoietic progenitors.
Gurumurthy et al. (2010) independently showed that the Lkb1 tumor suppressor is critical for the maintenance of energy homeostasis in hematopoietic cells. Lkb1 inactivation in adult mice causes loss of HSC quiescence followed by rapid depletion of all hematopoietic subpopulations. Lkb1-deficient bone marrow cells exhibited mitochondrial defects, alterations in lipid and nucleotide metabolism, and depletion of cellular ATP. The hematopoietic effects are largely independent of Lkb1 regulation of AMPK and mTOR signaling. Gurumurthy et al. (2010) concluded that their data defined a central role for Lkb1 in restricting HSC entry into cell cycle and in broadly maintaining energy homeostasis in hematopoietic cells through a novel metabolic checkpoint.
Gan et al. (2010) showed that Lkb1 has an essential role in HSC homeostasis. They demonstrated that ablation of Lkb1 in adult mice results in severe pancytopenia and subsequent lethality. Loss of Lkb1 leads to impaired survival and escape from quiescence of HSCs, resulting in exhaustion of the HSC pool and a marked reduction of HSC repopulating potential in vivo. Lkb1 deletion has an impact on cell proliferation in HSCs, but not on more committed compartments, pointing to context-specific functions for Lkb1 in hematopoiesis. The adverse impact of Lkb1 deletion on hematopoiesis was predominantly cell-autonomous and mTOR complex 1-independent, and involves multiple mechanisms converging on mitochondrial apoptosis and possibly downregulation of PGC1 coactivators (see 604517) and their transcriptional network, which have critical roles in mitochondrial biogenesis and function. Thus, Gan et al. (2010) concluded that Lkb1 serves as an essential regulator of HSCs and hematopoiesis, and more generally, points to the critical importance of coupling energy metabolism and stem cell homeostasis.
Using overexpression and knockdown studies with cultured rat and mouse hippocampal and cortical neurons, Matsuki et al. (2010) found that a signaling pathway containing Stk25 (602255), Lkb1, Strad, and the Golgi protein Gm130 (GOLGA2; 602580) promoted Golgi condensation and multiple axon outgrowth while inhibiting Golgi deployment into dendrites and dendritic growth. This signaling pathway acted in opposition to the reelin (RELN; 600514)-Dab1 (603448) pathway, which tended to inhibit Golgi condensation and axon outgrowth and favor Golgi deployment into dendrites and dendrite outgrowth.
AMPK is an alpha-beta-gamma heterotrimer activated by decreasing concentrations of adenosine triphosphate (ATP) and increasing AMP concentrations (summary by Oakhill et al., 2011). AMPK activation depends on phosphorylation of the alpha catalytic subunit on thr172 by kinases LKB1 or CaMKK-beta (CAMKK2; 615002), and this is promoted by AMP binding to the gamma subunit (602742). AMP sustains activity by inhibiting dephosphorylation of alpha-thr172, whereas ATP promotes dephosphorylation. Oakhill et al. (2011) found that adenosine diphosphate (ADP), like AMP, bound to gamma sites 1 and 3 and stimulated alpha-thr172 phosphorylation. However, in contrast to AMP, ADP did not directly activate phosphorylated AMPK. In this way, both ADP/ATP and AMP/ATP ratios contribute to AMPK regulation.
Denning et al. (2012) identified a mechanism of cell extrusion that is caspase-independent and that can eliminate a subset of the C. elegans cells programmed to die during embryonic development. In wildtype animals, these cells die soon after their generation through caspase-mediated apoptosis. However, in mutants lacking all 4 C. elegans caspase genes, these cells were eliminated by being extruded from the developing embryo into the extraembryonic space of the egg. The shed cells showed apoptosis-like cytologic and morphologic characteristics, indicating that apoptosis can occur in the absence of caspases in C. elegans. Denning et al. (2012) described a kinase pathway required for cell extrusion involving Par4, Strd1, and Mop25.1/25.2, the C. elegans homologs of the mammalian tumor suppressor kinase LKB1 and its binding partners STRAD-alpha (608626) and MO25-alpha (612174). The AMPK-related kinase Pig1, a possible target of the Par4-Strd1-Mop25 kinase complex, is also required for cell shedding. Pig1 promotes shed cell detachment by preventing the cell surface expression of cell adhesion molecules. Denning et al. (2012) concluded that their findings revealed a mechanism for apoptotic cell elimination that is fundamentally distinct from that of canonical programmed cell death.
Xu et al. (2013) found that knockdown of LKB1 or p114RHOGEF (ARHGEF18; 616432) in human bronchial epithelial (16HBE) cells led to similar apical junction defects. Immunoprecipitation of LKB1 resulted in coprecipitation of p114RHOGEF. Overexpression of LKB1 in 16HBE cells caused activation of RHOA; however, prior depletion of p114RHOGEF abrogated RHOA activation by LKB1. Depletion of either LKB1 or p114RHOGEF also abrogated calcium-dependent formation of mature apical junctions in 16HBE cells. Xu et al. (2013) concluded that both LKB1 and p114RHOGEF are required for the transition from primordial junctions to mature apical junctions.
By developing genetically engineered mouse models and primary pancreatic epithelial cells and by employing transcriptional, proteomics, and metabolic analyses, Kottakis et al. (2016) found that oncogenic cooperation between LKB1 loss and KRAS (190070) activation is fueled by pronounced mTOR (601231)-dependent induction of the serine-glycine-1-carbon pathway coupled to S-adenosylmethionine generation. At the same time, DNA methyltransferases are upregulated, leading to elevation in DNA methylation with particular enrichment at retrotransposon elements associated with their transcriptional silencing. Correspondingly, LKB1 deficiency sensitizes cells and tumors to inhibition of serine biosynthesis and DNA methylation.
Poffenberger et al. (2018) reported that heterozygous deletion of the Stk11 in T cells is sufficient to promote gastrointestinal polyposis. Polyps from mice deficient of Stk in T cells, Stk11+/- mice, and patients with Peutz-Jeghers syndrome (175200) display hallmarks of chronic inflammation, marked by inflammatory immune-cell infiltration, STAT3 (102582) activation, and increased expression of inflammatory factors associated with cancer progression (IL6, 147620; IL11, 147681; and CXCL2, 139110). Targeting either T cells, IL6, or STAT3 signaling reduced polyp growth in Stk11-heterozygous animals. Poffenberger et al. (2018) concluded that their results identified LKB1-mediated inflammation as a tissue-extrinsic regulator of intestinal polyposis in Peutz-Jeghers syndrome.
Crystal Structure
Zeqiraj et al. (2009) described the structure of the core heterotrimeric LKB1-STRAD-alpha-MO25-alpha (612174) complex, revealing an unusual allosteric mechanism of LKB1 activation. STRAD-alpha adopts a closed conformation typical of active protein kinases and binds LKB1 as a pseudosubstrate. STRAD-alpha and MO25-alpha promote the active conformation of LKB1, which is stabilized by MO25-alpha interacting with the LKB1 activation loop. Zeqiraj et al. (2009) suggested that this previously undescribed mechanism of kinase activation may be relevant to understanding the evolution of other pseudokinases, and also commented that the structure reveals how mutations found in Peutz-Jeghers (175200) syndrome and in various sporadic cancers impair LKB1 function.
Jenne et al. (1998) determined that the STK11 gene extends over 23 kb of genomic DNA and is composed of 9 exons, which are transcribed in telomere-to-centromere direction. The splice junctions of intron 2 deviate from the GT/AG rule with sequences indicative of a novel class of highly unusual eukaryotic introns.
Smith et al. (1999) found that the mouse Lkb1 gene consists of 10 exons covering approximately 15 kb.
At a distance of 190 kb proximal to marker D19S886 on chromosome 19p13.3, Jenne et al. (1998) identified the STK11 gene.
Smith et al. (1999) mapped the mouse Lkb1 gene to chromosome 10.
Peutz-Jeghers syndrome (PJS; 175200) is an autosomal dominant disorder characterized by melanocytic macules of the lips, buccal mucosa, and digits, multiple gastrointestinal hamartomatous polyps, and an increased risk of various neoplasms. Jenne et al. (1998) performed mutation analysis in 5 unrelated PJS patients and found mutations in STK11 in each. The finding of a rearrangement on initial mutation screening in a 3-generation PJS family focused interest on STK11. In this family, affected members carried an STK11 allele with a deletion of exons 4 and 5 and an inversion of exons 6 and 7 (602216.0001). In 4 other unrelated PJS patients, they found 3 nonsense mutations (602216.0002, 602216.0003, 602216.0004) and 1 acceptor splice site mutation (602216.0005). All 5 germline mutations were predicted to disrupt the function of the kinase domain. Jenne et al. (1998) concluded that germline mutations in STK11, probably in conjunction with acquired genetic defects of the second allele in somatic cells according to the Knudson model, caused the manifestations of PJS.
Hemminki et al. (1998) identified STK11, the gene on 19q mutant in individuals affected by PJS, as a previously unpublished anonymous cDNA clone in GenBank, LKB1, which showed strong homology to a cytoplasmic serine/threonine protein kinase in Xenopus, XEEK1 (Su et al., 1996), and weaker similarity to many other protein kinases. They found mutations in the STK11 gene in 11 of 12 unrelated families with PJS. Ten of the 11 were truncating mutations. All were heterozygous in the germline. Hemminki et al. (1998) commented that PJS was the first cancer susceptibility syndrome identified that is due to inactivating mutations in a protein kinase. Activation of kinase activity may be responsible for cancer susceptibility in multiple endocrine neoplasia type II (164761), familial renal papillary cancer (164860), and familial melanoma (155600).
In 2 Indian families, Mehenni et al. (1998) could find no mutations in the STK11 gene in patients with PJS; in 1 of these families they had previously detected linkage to markers on 19q13.3-q13.4.
To investigate the prevalence of STK11 germline mutations in PJS, Ylikorkala et al. (1999) studied samples from 33 unrelated PJS patients, including 8 nonfamilial sporadic patients, 20 familial patients, and 5 patients with unknown family history. They identified 19 germline mutations, 12 (60%) in familial and 4 (50%) in sporadic cases. STK11 mutations were not detected in 14 (42%) patients, indicating that the existence of additional minor PJS loci cannot be excluded. To demonstrate the putative STK11 kinase function and to study the consequences of STK11 mutations in PJS and sporadic tumors, Ylikorkala et al. (1999) analyzed the kinase activity of wildtype and mutant STK11 proteins. Whereas most of the small deletions or missense mutations resulted in loss-of-function alleles, 1 missense mutation (gly163 to asp; 602216.0011), previously identified in a sporadic testicular tumor (Avizienyte et al., 1998), demonstrated severely impaired but detectable kinase activity.
A teenaged girl with Peutz-Jeghers syndrome described as case 7 by Jeghers et al. (1949) died of pancreatic cancer in her early thirties. Guldberg et al. (1999) were prompted to search for STK11 somatic mutations in malignant melanomas because of the lentigines of the lips and oral mucosa that represent a cardinal feature of Peutz-Jeghers syndrome. In a study of cell lines in tumor samples from 35 patients with sporadic malignant melanoma, they identified 2 somatic mutations: a nonsense mutation (glu170 to ter; 602216.0018) causing exon skipping and intron retention, and a missense mutation (asp194 to tyr; 602216.0013) affecting an invariant residue in the catalytic subunit of STK11. Rowan et al. (1999) likewise postulated that the melanin spots of PJS patients are small benign tumors and that if mutations provide these lesions with a selective advantage, similar mutations might give a selective advantage to related malignant tumors, such as melanomas. Among 16 melanoma cell lines, 15 primary melanomas, and 19 metastases, Rowan et al. (1999) found 2 somatic mutations: a missense change (tyr49 to asp; 602216.0019) accompanied by allele loss in a cell line; and a missense change (gly135 to arg; 602216.0020), without a detected mutation in the other allele, in a primary tumor. They suspected both of these mutations to be pathogenic.
Su et al. (1999) found that of 53 PJS patients with cancer reported to that time, 6 (11%) were diagnosed with pancreatic adenocarcinoma, including case 7 in the report by Jeghers et al. (1949). Su et al. (1999) presented evidence that the STK11 gene plays a role in the development of both sporadic and familial (PJS) pancreatic and biliary cancers. They found that in sporadic cancers, the STK11 gene was somatically mutated in 5% of pancreatic cancers and in at least 6% of biliary cancers examined. In the patient with pancreatic cancer associated with PJS, there was inheritance of a mutated copy of the STK11 gene and somatic loss of the remaining wildtype allele.
When the syndromal association of melanin spots and intestinal polyps was first described, Jeghers et al. (1949) pointed out that it presumably reflected the pleiotropic effects of a single gene, not a syndrome due to closely linked genes of the sort that were later designated contiguous gene syndromes by Schmickel (1986). This was concluded on the basis of genetic principles, since even closely linked genes can get separated from each other. The mechanism of the pleiotropism was, however, unclear. Now that the polyps in the Peutz-Jeghers syndrome are known to be caused by a Knudson 2-hit mechanism, the melanin spots presumably represent a similar 2-hit mutation in melanoblasts, giving a spotted result. The reason for the characteristic location of the pigmented spots, like the reason for the predominant location of the intestinal polyps in the jejunum, is unclear. In the perioral and buccal areas and the intestine, there may be particular mutation-inciting factors predisposing to the second somatic 'hit.' Perhaps one such factor is pressure or irritation or some other physical factor.
Westerman et al. (1999) found novel STK11 mutations in 12 of 19 predominantly Dutch families with PJS. No mutation was found in the remaining 7 families. None of the mutations occurred in more than 1 family, and a number were demonstrated to have arisen de novo. The likelihood of locus heterogeneity was raised.
Nezu et al. (1999) characterized the basic biochemical properties of LKB1. By analysis of mutant LKB1 identified in PJS patients, they found that 1 of the mutants, SL26, a small in-frame deletion, did not lose its kinase function but altered its subcellular distribution to accumulate in the nucleus only, whereas wildtype LKB1 shows both nuclear and cytoplasmic localization. Domain mapping of the nuclear targeting signal of LKB1 assigned it to its N-terminal side. Furthermore, it was shown that LKB1 also has a cytoplasmic retention ability that was defective and pathogenic in the SL26 mutant. Nezu et al. (1999) speculated that subcellular distribution of LKB1 is regulated in the balance of these 2 forces, importation into the nucleus and retention within the cytoplasm, and that the cytoplasmic retention ability is necessary for LKB1 to fulfill its normal function.
Since patients with PJS are at increased risk of benign and malignant ovarian tumors, particularly granulosa cell tumors, and because loss of heterozygosity (LOH) has been reported for 19p13.3 in about 50% of ovarian cancers, Wang et al. (1999) screened 10 ovarian cancers with LOH for chromosome 19, 35 other ovarian cancers, and 12 granulosa cell tumors of the ovary for somatic mutations in the LKB1 gene. No variants were detected in any of the adenocarcinomas. Two mutations, a missense mutation affecting the putative start codon and a silent change in exon 7, were detected in 1 of the granulosa cell tumors. Like BRCA1 (113705) and BRCA2 (600185), therefore, it appeared that LKB1 mutations can cause ovarian tumors when present in the germline, but occur rarely as somatic mutations causing sporadic tumors. Wang et al. (1999) concluded that the allele loss at 19p13.3 in ovarian cancers almost certainly targets a different gene from LKB1.
Abed et al. (2001) reported that mutation screening at the RNA level of the STK11 gene in PJS revealed complex splicing abnormalities. They suggested that since germinal mutations have been found in no more than 60% of cases, RNA-based screening procedures in peripheral blood cells should be performed in cases of PJS where no mutations are identified at the DNA level. They described a compound heterozygous PJS patient who carried 2 different mutations in intron 1 of the STK11 gene on separate alleles. Each of the 2 mutations was transmitted individually to 1 of his 2 children; 1 of the children had spots on the lips, whereas the other did not demonstrate lentigines of the lips and oral mucosa at the age of 8 years.
In Australia, Scott et al. (2002) studied 5 unrelated probands and 9 unrelated patients with PJS for mutations in the STK11 gene. They identified only 3 unequivocally causative mutations, 2 deletions and 1 splice site mutation, in 3 probands. Two missense mutations were considered 'likely to be causative;' see 602216.0021. In a large 3-generation family, linkage analysis yielded a multipoint lod score of 4.5 with the STK11 region; however, no mutations were identified in the coding region of the STK11 gene.
Amos et al. (2004) screened 42 independent probands for mutations in the STK11 gene and detected mutations in 22 of 32 (69%) probands with PJS and 0 of 10 probands referred to rule out PJS. In a total of 51 participants with PJS, the authors found gastric polyps to be very common, with a median age at onset of 16 years. Individuals with missense mutations had a significantly later time to onset of first polypectomy (p = 0.04) and of other symptoms compared with those participants with either truncating mutations or no detectable mutation. Amos et al. (2004) concluded that STK11 mutation analysis should be restricted to individuals who meet PJS criteria or their close relatives.
Le Meur et al. (2004) reported a family with typical features of PJS, including melanin spots of the oral mucosa, gastrointestinal hamartomatous polyps, and breast and colon cancer. Using quantitative multiplex PCR of short fluorescent fragments of the 19p13 region, they identified an approximately 250-kb heterozygous deletion that completely removed the STK11 locus. Le Meur et al. (2004) stated that this was the first report of a complete germline deletion of STK11 and suggested that the presence of such large genomic deletions should be considered in PJS families without detectable point mutations of STK11.
In a study of 132 PJS patients with or without cancer who had mutations in the STK11 gene, Schumacher et al. (2005) found that mutations in the part of the gene involved in ATP binding and catalysis were rarely associated with cancer, whereas mutations in the part of the gene involved in substrate recognition were more frequently associated with malignancies. PJS patients with breast cancers had predominantly truncating mutations.
In a patient with PJS and a primary gastric cancer (see 137215), Shinmura et al. (2005) identified heterozygosity for a germline deletion mutation of the STK11 gene (602216.0022) encoding a truncated protein. No inactivation of the wildtype allele by somatic mutation, chromosomal deletion, or hypermethylation at the 5-prime CpG site of STK11 was detected in the gastric carcinoma. The patient's sister also had PJS and died of gastric carcinoma in her twenties. Shinmura et al. (2005) stated that this was the first report of an STK11 germline mutation in a PJS patient with gastric carcinoma.
Aretz et al. (2005) performed a mutation analysis of the STK11 gene in 71 patients, of whom 56 met the critical criteria for PJS and 12 were presumed to have PJS because of mucocutaneous pigmentation only or bowel problems due to isolated PJS-type polyps. No clinical information was available for the remaining 3 patients. By direct sequencing of the coding region of the STK11 gene, they identified point mutations in 37 (52%) of 71 patients. In the remaining 34 patients, the multiplex ligation-dependent probe amplification (MLPA) method detected deletions in 17 patients. In 4 patients the deletion extended over all 10 exons, and in 8 patients only the promoter region in exon 1 was deleted. The remaining deletions encompassed exons 2-10 (2 patients), exons 2-3, exons 4-5, or exon 8 (1 patient, respectively). When only patients who met the clinical criteria for PJS were considered, the overall mutation detection rate increased to 94% (64% point mutations and 30% large deletions). No mutation was identified in any of the 12 presumed cases. Thus, they found that approximately one-third of the patients who met the clinical PJS criteria exhibited large genomic deletions that were readily detectable by MLPA. Since there may still be other mutations in the STK11 gene that were not detectable by the methods used by Aretz et al. (2005), they questioned whether a second PJS locus exists at all.
Forcet et al. (2005) investigated the functional consequences of LKB1 missense mutations (see, e.g., 602216.0024) in the C-terminal noncatalytic region. C-terminal mutations did not disrupt LKB1 kinase activity or interfere with LKB1-induced growth arrest; however, they lessened LKB1-mediated activation of the AMP-activated protein kinase (AMPK; 602739) and impaired downstream signaling. C-terminal mutations compromised LKB1 ability to establish and maintain polarity of both intestinal epithelial cells and migrating astrocytes. Mutation analysis revealed that the LKB1 tail exerted an essential function in the control of cell polarity. Forcet et al. (2005) proposed a crucial regulatory role for the LKB1 C-terminal region, and suggested that LKB1 tumor suppressor activity is likely to depend on the regulation of AMPK signaling and cell polarization.
Chow et al. (2006) screened 33 PJS patients from unrelated families, employing a combination of denaturing high-performance liquid chromatography, direct DNA sequencing, and the multiplex ligation probe amplification (MLPA) assay to identify deleterious changes in the STK11 gene. The results revealed that 24 (73%) of patients harbored pathogenic mutations in the STK11 gene, including 10 (36%) with exonic or whole-gene deletions. No phenotypic differences were identified in patients harboring large deletions in the STK11 gene compared to patients harboring missense or nonsense mutations. Chow et al. (2006) concluded that most if not all PJS is attributable to mutations in the STK11 gene, perhaps including undiscovered changes in promoter or enhancer sequences or other cryptic changes.
Ylikorkala et al. (2001) generated mice deficient in Lkb1 by targeted disruption. Lkb1 -/- mice die at midgestation, with the embryos showing neural tube defects, mesenchymal cell death, and vascular abnormalities. Extraembryonic development was also severely affected; the mutant placentas exhibited defective labyrinth-layer development and the fetal vessels failed to invade the placenta. These phenotypes were associated with tissue-specific deregulation of vascular endothelial growth factor (VEGF; 192240) expression, including a marked increase in the amount of VEGF mRNA. Moreover, VEGF production in cultured Lkb1 -/- fibroblasts was elevated in both normoxic and hypoxic conditions. Ylikorkala et al. (2001) concluded that their findings place Lkb1 in the VEGF signaling pathway and suggested that vascular defects accompanying Lkb1 loss are mediated at least in part by VEGF.
To investigate the role of LKB1 in PJS (175200) phenotypes, Miyoshi et al. (2002) introduced a germline mutation in the mouse Lkb1 gene by homologous recombination in mouse embryonic stem cells. In most heterozygous mice over 20 weeks of age, hamartomatous polyps developed in the glandular stomach, often in the pyloric region. Small intestinal hamartomas also developed in approximately one-third of the heterozygous mice over 50 weeks of age. Genomic PCR and sequence analysis showed that all hamartomas retained both the wildtype and the targeted Lkb1 alleles, indicating that allelic loss of the wildtype Lkb1 was not the cause of polyp formation. Moreover, the Lkb1 protein level was not reduced in hamartomatous polyps compared with that in Lkb1 heterozygous normal gastric mucosa. In addition, the remaining allele showed no missense mutations in the coding sequence and did not produce truncated LKB1 in the hamartoma. Taken together, these data suggested that the wildtype Lkb1 gene is expressed in the hamartoma at the haploid amount. Accordingly, the gastrointestinal hamartomas appear to develop because of Lkb1 haploinsufficiency. Although additional genetic events may be critical in hamartoma and adenocarcinoma development, these data strongly suggest that the initiation of polyposis is not the result of loss of heterozygosity in Lkb1.
Jishage et al. (2002) constructed a knockout mutation of the Lkb1 gene in mice to determine whether it is the causative gene of PJS and to examine its biologic role. Homozygous-null mice died in utero between 8.5 and 9.5 days postcoitum. At 9.0 days postcoitum, null embryos were generally smaller than their age-matched littermates, showed developmental retardation, and did not undergo embryonic turning. Multiple gastric adenomatous polyps were observed in 10- to 14-month-old heterozygous mice. The results indicated that functional LKB1 is required for normal embryogenesis and that it is related to tumor development.
Bardeesy et al. (2002) generated Lkb1 knockout and heterozygous mice by targeted disruption. Lkb1 heterozygotes developed intestinal polyps identical to those seen in individuals affected with PJS. Consistent with this in vivo tumor suppressor function, Lkb1 deficiency prevented culture-induced senescence without loss of Ink4a/Arf (600160) or p53. Despite compromised mortality, Lkb1 -/- mouse embryonic fibroblasts showed resistance to transformation by activated Hras (190020) either alone or with immortalizing oncogenes. This phenotype is in agreement with the paucity of mutations in Ras seen in PJS polyps and suggests that loss of LKB1 function as an early neoplastic event renders cells resistant to subsequent oncogene-induced transformation. In addition, the Lkb1 transcriptome showed modulation of factors linked to angiogenesis, extracellular matrix remodeling, cell adhesion, and inhibition of Ras transformation. Bardeesy et al. (2002) concluded that taken together, their data rationalized several features of PJS polyposis, notably its peculiar histopathologic presentation and limited malignant potential, and placed Lkb1 in a distinct class of tumor suppressors.
Rossi et al. (2002) generated mice heterozygous for a targeted inactivating allele of Lkb1. The mice developed severe gastrointestinal polyposis. The polyps were hamartomas histologically indistinguishable from polyps resected from PJS patients, indicating that Lkb1 heterozygous mice model human PJS polyposis. There was no evidence of inactivation of the remaining wildtype Lkb1 allele in Lkb1 heterozygous-associated polyps. Moreover, polyps and other tissues in heterozygote animals exhibited reduced Lkb1 levels and activity, indicating that Lkb1 was haploinsufficient for tumor suppression. Analysis of the molecular mechanisms characterizing Lkb1 heterozygous polyposis revealed that cyclooxygenase-2 (COX2; 600262) was highly upregulated in mouse polyps concomitantly with activation of the extracellular signal-regulated kinases 1 (ERK1; 601795) and 2 (ERK2; 176948). COX2 was also highly upregulated in most of a large series of human PJS polyps subsequently examined. These findings thereby identified COX2 as a potential target for chemoprevention in PJS patients.
Shaw et al. (2005) created conditional knockout mice in which Lkb1 was deleted in adult liver only. These mice showed nearly complete loss of adenosine monophosphate (AMP)-activated protein kinase (AMPK; see 600497) activity. Loss of Lkb1 function resulted in hyperglycemia with increased gluconeogenic and lipogenic gene expression. In Lkb1-deficient livers, Torc2 (608972), a transcriptional coactivator of CREB (123810), was dephosphorylated and entered the nucleus, driving the expression of PPAR-gamma coactivator 1-alpha (PGC1A; 604517), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA for Torc2 reduced Pgc1a expression and normalized blood glucose levels in mice with deleted liver Lkb1, indicating that TORC2 is a critical target of LKB1-AMPK signals in the regulation of gluconeogenesis. Finally, Shaw et al. (2005) showed that metformin, a widely prescribed type 2 diabetes therapy, requires LKB1 in the liver to lower blood glucose levels.
Yang et al. (2017) found that mice with a deletion of Lkb1 specifically in regulatory T (Treg) cells developed a fatal inflammatory disease characterized by Th2-type-dominant responses. Treg cell survival and mitochondrial fitness and metabolism were disrupted in mutant mice, and aberrant expression of immune regulatory molecules, such as Pd1 (PDCD1; 600244), Gitr (TNFRSF18; 603905), and Ox40 (TNFRSF4; 600315) was observed. Lkb1 function in Treg cells was independent of Ampk signaling and the Mtorc1-Hif1a (603348) axis, but Lkb1 function contributed to activation of beta-catenin (CTNNB1; 116806) signaling for control of Pd1 and Tnfr proteins. Blockade of Pd1 activity enhanced the ability of Lkb1-deficient Treg cells to suppress Th2 responses and the interplay with dendritic cells primed by Tslp (607003). Yang et al. (2017) concluded that Treg cells use LKB1 signaling to coordinate their metabolic and immunological homeostasis and to prevent apoptotic and functional exhaustion.
Lin et al. (2012) reported that acetylation and deacetylation of the catalytic subunit of the adenosine monophosphate-activated protein kinase (AMPK), PRKAA1 (602739), a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 (601241) and p300. Deacetylation of AMPK enhanced physical interaction with the upstream kinase LKB1 (602216), leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. The authors later found that the Methods section of their article was inaccurate. Because they could not reproduce all of their results, they retracted the article.
In a 3-generation family, Jenne et al. (1998) found that members with Peutz-Jeghers syndrome (PJS; 175200) were heterozygous for a deletion of exons 4 and 5 and an inversion of exons 6 and 7 in the STK11 gene. Codon 155 was the last wildtype codon and codons 156 through 307 were deleted.
In a patient with Peutz-Jeghers syndrome (PJS; 175200), Jenne et al. (1998) identified a heterozygous 759C-A transversion, resulting in a change of codon 253 from TAC (tyr) to TAA (stop) (Y253X). The last wildtype codon was number 252 in exon 6.
In a patient with Peutz-Jeghers syndrome (PJS; 175200), Jenne et al. (1998) found that the STK11 gene carried a heterozygous deletion of nucleotide 843G, resulting in frameshift and stop at codon 286. Codon 280 was the last wildtype codon.
In a patient with Peutz-Jeghers syndrome (PJS; 175200), Jenne et al. (1998) identified a heterozygous 4-bp deletion (716delGGTC) in exon 5 of the STK11 gene. The deletion caused a frameshift with a stop at codon 285; the last wildtype codon was 240.
In a patient with Peutz-Jeghers syndrome (PJS; 175200), Jenne et al. (1998) identified a heterozygous splice site mutation that changed the strictly conserved splice acceptor site at the 3-prime end of intron 3 from AG to AA. Because mRNA was not available from this patient, Jenne et al. (1998) could not demonstrate the most likely consequence of this mutation, the joining of exon 3 with exon 5, which would result in a reading frameshift after residue 155 and subsequent termination of the altered protein sequence after residue 241.
In their patient SL32 with Peutz-Jeghers syndrome (PJS; 175200), Hemminki et al. (1998) identified a heterozygous lys84-to-ter mutation (K84X) in the STK11 gene.
In their patient SL31 with Peutz-Jeghers syndrome (PJS; 175200), Hemminki et al. (1998) found a heterozygous deletion of nucleotides 277 and 278 of the STK11 mRNA causing a frameshift and premature termination at codon 283.
In 1 of their 12 families with Peutz-Jeghers syndrome (PJS; 175200), Hemminki et al. (1998) found a heterozygous T-to-C transition in the STK11 gene, resulting in a leu67-to-pro (L67P) substitution.
In their patient SL26 with Peutz-Jeghers syndrome (PJS; 175200), Hemminki et al. (1998) identified a heterozygous 9-bp deletion, converting 4 codons (303 to 306) from ile-arg-gln-his to asn.
In their patient SL12 with Peutz-Jeghers syndrome (PJS; 175200), Hemminki et al. (1998) found a heterozygous glu57-to-ter (E57X) nonsense mutation in the STK11 gene.
Avizienyte et al. (1998) identified a somatic gly163-to-asp mutation of the STK11 gene in a case of sporadic testicular carcinoma (273300). In further studies, Ylikorkala et al. (1999) found that this mutation was associated with severely impaired but detectable kinase activity.
In the family with Peutz-Jeghers syndrome (PJS; 175200) originally studied by McKusick, who contributed to the publication of Jeghers et al. (1949), Gruber et al. (1998) found linkage to 19p13.3. By sequencing genomic DNA they identified a 1407delC germline mutation in the STK11 gene. Three affected family members were found to be heterozygous for the mutation, and 3 unaffected individuals carried 2 wildtype alleles.
In a sample of cell lines and tumor specimens from 35 patients with sporadic malignant melanoma (see 155600), Guldberg et al. (1999) identified 2 somatic mutations, 1 of which, an asp194-to-tyr substitution, affected an invariant residue in the catalytic subunit of STK11.
In the Dutch family in which Peutz (1921) first described the association of gastrointestinal polyps with mucocutaneous melanin spots, now known as Peutz-Jeghers syndrome (PJS; 175200), Westerman et al. (1999) found that affected individuals were heterozygous for a T insertion at nucleotide 535 in codon 66 of the STK11 gene, resulting in a frameshift that produced a stop signal at codon 162 in exon 4. All affected patients, but none of their unaffected relatives, carried this mutation.
In a series of pancreatic cancers with loss of heterozygosity (LOH), Su et al. (1999) found that 3 had mutations in the STK11 gene: 1 nonsense and 2 frameshift mutations. The nonsense mutation, tyr36 to ter, which occurred in exon 1, and 1 of the frameshift mutations (602216.0016), which occurred in exon 5, were within the catalytic kinase domain of STK11 (codons 37 to 314).
In a pancreatic cancer that showed loss of heterozygosity of 1 allele in the 19p13.3 region, Su et al. (1999) found that the other allele carried somatic deletion of a cytosine in codon 217 in exon 5, converting CCG to CGG and causing a frameshift.
In a pancreatic cancer that showed loss of heterozygosity of 1 allele in the 19p13.3 region, Su et al. (1999) found that the other allele carried a somatic deletion of an adenine in codon 312 of exon 8, converting AAA to AAC and causing a frameshift. This mutation would potentially affect the function of the regulatory domain of STK1 that comprises the 119 residues at the C terminus.
In a cell line prepared from a tumor in a patient with sporadic melanoma (see 155600), Guldberg et al. (1999) identified a glu170-to-ter mutation causing exon skipping and intron retention.
In a melanoma cell line derived from a primary lesion (see 155600), Rowan et al. (1999) found a tyr49-to-asp (Y49D) missense mutation in the STK11 gene product. No wildtype STK11 allele was detected on sequencing, strongly suggesting mutation of the other allele by loss of heterozygosity (LOH).
In a primary melanoma (see 155600), Rowan et al. (1999) found a somatic gly135-to-arg (G135R) missense change in the STK11 protein. The mutation was found in heterozygous state.
In an Australian patient diagnosed with Peutz-Jeghers syndrome (PJS; 175200) at the age of 42 years, Scott et al. (2002) identified a heterozygous 717G-C transversion in exon 5 of the STK11 gene, resulting in a trp239-to-cys (W239C) substitution. Although the features of Peutz-Jeghers syndrome were typical, the late onset suggested reduced penetrance.
In a patient with Peutz-Jeghers syndrome (PJS; 175200) and a primary gastric cancer (137215), Shinmura et al. (2005) identified heterozygosity for an 890G deletion in exon 7 of the STK11 gene, resulting in a frameshift at codon arg297, the introduction of 38 novel amino acids, and premature termination at 334 amino acids. No inactivation of the wildtype allele by somatic mutation, chromosomal deletion, or hypermethylation at the 5-prime CpG site of STK11 was detected in the gastric carcinoma. The patient's sister also had PJS and died of gastric carcinoma in her twenties. Shinmura et al. (2005) stated that this was the first report of an STK11 germline mutation in a PJS patient with gastric carcinoma.
In a 20-year-old female patient with Peutz-Jeghers syndrome (PJS; 175200) and gastrointestinal hamartomatous polyps, Hernan et al. (2004) identified a de novo heterozygous germline 3256C-G transversion in exon 6 of the STK11 gene, resulting in a tyr246-to-ter (Y246X) substitution, predicted to cause premature termination. This mutation was not found in her parents. Comparison of melting curve profiles obtained from DNA from the patient's lymphocytes and hamartomatous polyps showed no differences, indicative of a heterozygous mutation rather than loss of heterozygosity in the polyps. Hernan et al. (2004) suggested that biallelic inactivation of STK11 is not necessarily required for hamartoma formation in PJS patients.
This variant, formerly titled PEUTZ-JEGHERS SYNDROME, has been reclassified based on a review of the gnomAD database by Hamosh (2020).
Forcet et al. (2005) stated that a heterozygous C-to-G transversion in exon 8 of the STK11 gene, resulting in a phe354-to-leu (F354L) substitution, had been identified in a 14-year-old proband with Peutz-Jeghers syndrome (PJS; 175200). The boy displayed a large number of pigmented macules without evidence of intestinal polyps. The proband's mother, who transmitted the germline mutation, was asymptomatic.
Hamosh (2020) noted that the F354L mutation was present in 1,383 of 276,376 alleles and in 17 homozygotes in the gnomAD database (March 18, 2020).
Abed, A. A., Gunther, K., Kraus, C., Hohenberger, W., Ballhausen, W. G. Mutation screening at the RNA level of the STK11/LKB1 gene in Peutz-Jeghers syndrome reveals complex splicing abnormalities and a novel mRNA isoform (STK11 c.597/598insIVS4). Hum. Mutat. 18: 397-410, 2001. [PubMed: 11668633] [Full Text: https://doi.org/10.1002/humu.1211]
Amos, C. I., Keitheri-Cheteri, M. B., Sabripour, M., Wei, C., McGarrity, T. J., Seldin, M. F., Nations, L., Lynch, P. M., Fidder, H. H., Friedman, E., Frazier, M. L. Genotype-phenotype correlations in Peutz-Jeghers syndrome. J. Med. Genet. 41: 327-333, 2004. [PubMed: 15121768] [Full Text: https://doi.org/10.1136/jmg.2003.010900]
Aretz, S., Stienen, D., Uhlhaas, S., Loff, S., Back, W., Pagenstecher, C., McLeod, D. R., Graham, G. E., Mangold, E., Santer, R., Propping, P., Friedl, W. High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome. Hum. Mutat. 26: 513-519, 2005. [PubMed: 16287113] [Full Text: https://doi.org/10.1002/humu.20253]
Avizienyte, E., Roth, S., Loukola, A., Hemminki, A., Lothe, R. A., Stenwig, A. E., Fossa, S. D., Salovaara, R., Aaltonen, L. A. Somatic mutations in LKB1 are rare in specific colorectal and testicular tumors. Cancer Res. 58: 2087-2090, 1998. [PubMed: 9605748]
Baas, A. F., Boudeau, J., Sapkota, G. P., Smit, L., Medema, R., Morrice, N. A., Alessi, D. R., Clevers, H. C. Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. EMBO J. 22: 3062-3072, 2003. [PubMed: 12805220] [Full Text: https://doi.org/10.1093/emboj/cdg292]
Baas, A. F., Kuipers, J., van der Wel, N. N., Batlle, E., Koerten, H. K., Peters, P. J., Clevers, H. C. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 116: 457-466, 2004. [PubMed: 15016379] [Full Text: https://doi.org/10.1016/s0092-8674(04)00114-x]
Bardeesy, N., Sinha, M., Hezel, A. F., Signoretti, S., Hathaway, N. A., Sharpless, N. E., Loda, M., Carrasco, D. R., DePinho, R. A. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419: 162-167, 2002. [PubMed: 12226664] [Full Text: https://doi.org/10.1038/nature01045]
Chow, E., Meldrum, C. J., Crooks, R., Macrae, F., Spigelman, A. D., Scott, R. J. An updated mutation spectrum in an Australian series of PJS patients provides further evidence for only one gene locus. Clin. Genet. 70: 409-414, 2006. [PubMed: 17026623] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00704.x]
Denning, D. P., Hatch, V., Horvitz, H. R. Programmed elimination of cells by caspase-independent cell extrusion in C. elegans. Nature 488: 226-230, 2012. [PubMed: 22801495] [Full Text: https://doi.org/10.1038/nature11240]
Forcet, C., Etienne-Manneville, S., Gaude, H., Fournier, L., Debilly, S., Salmi, M., Baas, A., Olschwang, S., Clevers, H ., Billaud, M. Functional analysis of Peutz-Jeghers mutations reveals that the LKB1 C-terminal region exerts a crucial role in regulating both the AMPK pathway and cell polarity. Hum. Molec. Genet. 14: 1283-1292, 2005. [PubMed: 15800014] [Full Text: https://doi.org/10.1093/hmg/ddi139]
Gan, B., Hu, J., Jiang, S., Liu, Y., Sahin, E., Zhuang, L., Fletcher-Sananikone, E., Colla, S., Wang, Y. A., Chin, L., DePinho, R. A. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 468: 701-704, 2010. [PubMed: 21124456] [Full Text: https://doi.org/10.1038/nature09595]
Gruber, S. B., Entius, M. M., Petersen, G. M., Laken, S. J., Longo, P. A., Boyer, R., Levin, A. M., Mujumdar, U. J., Trent, J. M., Kinzler, K. W., Vogelstein, B., Hamilton, S. R., Polymeropoulos, M. H., Offerhaus, G. J., Giardiello, F. M. Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. Cancer Res. 58: 5267-5270, 1998. [PubMed: 9850045]
Guldberg, P., thor Straten, P., Ahrenkiel, V., Seremet, T., Kirkin, A. F., Zeuthen, J. Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma. Oncogene 18: 1777-1780, 1999. [PubMed: 10208439] [Full Text: https://doi.org/10.1038/sj.onc.1202486]
Gurumurthy, S., Xie, S. Z., Alagesan, B., Kim, J., Yusuf, R. Z., Saez, B., Tzatsos, A., Ozsolak, F., Milos, P., Ferrari, F., Park, P. J., Shirihai, O. S., Scadden, D. T., Bardeesy, N. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468: 659-663, 2010. Note: Erratum: Nature 476: 114 only, 2011. [PubMed: 21124451] [Full Text: https://doi.org/10.1038/nature09572]
Hamosh, A. Personal Communication. Baltimore, Md. 3/18/2020.
Hemminki, A., Markie, D., Tomlinson, I., Avizienyte, E., Roth, S., Loukola, A., Bignell, G., Warren, W., Aminoff, M., Hoglund, P., Jarvinen, H., Kristo, P., Pelin, K., Ridanpaa, M., Salovaara, R., Toro, T., Bodmer, W., Olschwang, S., Olsen, A. S., Stratton, M. R., de la Chapelle, A., Aaltonen, L. A. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391: 184-187, 1998. [PubMed: 9428765] [Full Text: https://doi.org/10.1038/34432]
Hemminki, A., Tomlinson, I., Markie, D., Jarvinen, H., Sistonen, P., Bjorkqvist, A.-M., Knuutila, S., Salovaara, R., Bodmer, W., Shibata, D., de la Chapelle, A., Aaltonen, L. A. Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis. Nature Genet. 15: 87-90, 1997. [PubMed: 8988175] [Full Text: https://doi.org/10.1038/ng0197-87]
Hernan, I., Roig, I., Martin, B., Gamundi, M. J., Martinez-Gimeno, M., Carballo, M. De novo germline mutation in the serine-threonine kinase STK11/LKB1 gene associated with Peutz-Jeghers syndrome. Clin. Genet. 66: 58-62, 2004. [PubMed: 15200509] [Full Text: https://doi.org/10.1111/j.0009-9163.2004.00266.x]
Jeghers, H., McKusick, V. A., Katz, K. H. Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits. New Eng. J. Med. 241: 993-1005 and 1031-1036, 1949. [PubMed: 15399020] [Full Text: https://doi.org/10.1056/NEJM194912222412501]
Jenne, D. E., Reimann, H., Nezu, J., Friedel, W., Loff, S., Jeschke, R., Muller, O., Back, W., Zimmer, M. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nature Genet. 18: 38-43, 1998. [PubMed: 9425897] [Full Text: https://doi.org/10.1038/ng0198-38]
Ji, H., Ramsey, M. R., Hayes, D. N., Fan, C., McNamara, K., Kozlowski, P., Torrice, C., Wu, M. C., Shimamura, T., Perera, S. A., Liang, M.-C., Cai, D., and 22 others. LKB1 modulates lung cancer differentiation and metastasis. Nature 448: 807-810, 2007. [PubMed: 17676035] [Full Text: https://doi.org/10.1038/nature06030]
Jishage, K., Nezu, J., Kawase, Y., Iwata, T., Watanabe, M., Miyoshi, A., Ose, A., Habu, K., Kake, T., Kamada, N., Ueda, O., Kinoshita, M., Jenne, D. E., Shimane, M., Suzuki, H. Role of Lkb1, the causative gene of Peutz-Jegher's (sic) syndrome, in embryogenesis and polyposis. Proc. Nat. Acad. Sci. 99: 8903-8908, 2002. [PubMed: 12060709] [Full Text: https://doi.org/10.1073/pnas.122254599]
Karuman, P., Gozani, O., Odze, R. D., Zhou, X. C., Zhu, H., Shaw, R., Brien, T. P., Bozzuto, C. D., Ooi, D., Cantley, L. C., Yuan, J. The Peutz-Jegher (sic) gene product LKB1 is a mediator of p53-dependent cell death. Molec. Cell 7: 1307-1319, 2001. [PubMed: 11430832] [Full Text: https://doi.org/10.1016/s1097-2765(01)00258-1]
Katajisto, P., Vaahtomeri, K., Ekman, N., Ventela, E., Ristimaki, A., Bardeesy, N., Feil, R., DePinho, R. A., Makela, T. P. LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis. Nature Genet. 40: 455-459, 2008. [PubMed: 18311138] [Full Text: https://doi.org/10.1038/ng.98]
Kottakis, F., Nicolay, B. N., Roumane, A., Karnik, R., Gu, H., Nagle, J. M., Boukhali, M., Hayward, M. C., Li, Y. Y., Chen, T., Liesa, M., Hammerman, P. S., Wong, K. K., Hayes, D. N., Shirihai, O. S., Dyson, N. J., Haas, W., Meissner, A., Bardeesy, N. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature 539: 390-395, 2016. Note: Erratum: Nature 575: E5, 2019. [PubMed: 27799657] [Full Text: https://doi.org/10.1038/nature20132]
Le Meur, N., Martin, C., Saugier-Veber, P., Joly, G., Lemoine, F., Moirot, H., Rossi, A., Bachy, B., Cabot, A., Joly, P., Frebourg, T. Complete germline deletion of the STK11 gene in a family with Peutz-Jeghers syndrome. Europ. J. Hum. Genet. 12: 415-418, 2004. [PubMed: 14970844] [Full Text: https://doi.org/10.1038/sj.ejhg.5201155]
Lin, Y., Kiihl, S., Suhail, Y., Liu, S.-Y., Chou, Y., Kuang, Z., Lu, J., Khor, C. N., Lin, C.-L., Bader, J. S., Irizarry, R., Boeke, J. D. Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK. Nature 482: 251-255, 2012. Note: Retraction: Nature 503: 146 only, 2013. [PubMed: 22318606] [Full Text: https://doi.org/10.1038/nature10804]
Martin, S. G., St Johnston, D. A role for Drosophila LKB1 in anterior-posterior axis formation and epithelial polarity. Nature 421: 379-384, 2003. [PubMed: 12540903] [Full Text: https://doi.org/10.1038/nature01296]
Matsuki, T., Matthews, R. T., Cooper, J. A., van der Brug, M. P., Cookson, M. R., Hardy, J. A., Olson, E. C., Howell, B. W. Reelin and Stk25 have opposing roles in neuronal polarization and dendritic Golgi deployment. Cell 143: 826-836, 2010. [PubMed: 21111240] [Full Text: https://doi.org/10.1016/j.cell.2010.10.029]
Mehenni, H., Gehrig, C., Nezu, J., Oku, A., Shimane, M., Rossier, C., Guex, N., Blouin, J.-L., Scott, H. S., Antonarakis, S. E. Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity. Am. J. Hum. Genet. 63: 1641-1650, 1998. [PubMed: 9837816] [Full Text: https://doi.org/10.1086/302159]
Mehenni, H., Lin-Marq, N., Buchet-Poyau, K., Reymond, A., Collart, M. A., Picard, D., Antonarakis, S. E. LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes. Hum. Molec. Genet. 14: 2209-2219, 2005. [PubMed: 15987703] [Full Text: https://doi.org/10.1093/hmg/ddi225]
Miyoshi, H., Nakau, M., Ishikawa, T., Seldin, M. F., Oshima, M., Taketo, M. M. Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res. 62: 2261-2266, 2002. [PubMed: 11956081]
Nakada, D., Saunders, T. L., Morrison, S. J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468: 653-658, 2010. [PubMed: 21124450] [Full Text: https://doi.org/10.1038/nature09571]
Nezu, J., Oku, A., Shimane, M. Loss of cytoplasmic retention ability of mutant LKB1 found in Peutz-Jeghers syndrome patients. Biochem. Biophys. Res. Commun. 261: 750-755, 1999. [PubMed: 10441497] [Full Text: https://doi.org/10.1006/bbrc.1999.1047]
Oakhill, J. S., Steel, R., Chen, Z.-P., Scott, J. W., Ling, N., Tam, S., Kemp, B. E. AMPK is a direct adenylate charge-regulated protein kinase. Science 332: 1433-1435, 2011. [PubMed: 21680840] [Full Text: https://doi.org/10.1126/science.1200094]
Peutz, J. L. A. Very remarkable case of familial polyposis of mucous membrane of intestinal tract and nasopharynx accompanied by peculiar pigmentations of skin and mucous membrane. (Dutch). Nederl. Maandschr. Geneesk. 10: 134-146, 1921.
Poffenberger, M. C., Metcalfe-Roach, A., Aguilar, E., Chen, J., Hsu, B. E., Wong, A. H., Johnson, R. M., Flynn, B., Samborska, B., Ma, E. H., Gravel, S.-P., Tonelli, L., and 12 others. LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis. Science 361: 406-411, 2018. [PubMed: 30049881] [Full Text: https://doi.org/10.1126/science.aan3975]
Rossi, D. J., Ylikorkala, A., Korsisaari, N., Salovaara, R., Luukko, K., Launonen, V., Henkemeyer, M., Ristimaki, A., Aaltonen, L. A., Makela, T. P. Induction of cyclooxygenase-2 in a mouse model of Peutz-Jeghers polyposis. Proc. Nat. Acad. Sci. 99: 12327-12332, 2002. [PubMed: 12218179] [Full Text: https://doi.org/10.1073/pnas.192301399]
Rowan, A., Bataille, V., MacKie, R., Healy, E., Bicknell, D., Bodmer, W., Tomlinson, I. Somatic mutations in the Peutz-Jegners (sic) (LKB1/STKII) (sic) gene in sporadic malignant melanomas. J. Invest. Derm. 112: 509-511, 1999. [PubMed: 10201537] [Full Text: https://doi.org/10.1046/j.1523-1747.1999.00551.x]
Schmickel, R. D. Chromosomal deletions and enzyme deficiencies. J. Pediat. 108: 244-246, 1986. [PubMed: 3944710] [Full Text: https://doi.org/10.1016/s0022-3476(86)80991-x]
Schumacher, V., Vogel, T., Leube, B., Driemel, C., Goecke, T., Moslein, G., Royer-Pokora, B. STK11 genotyping and cancer risk in Peutz-Jeghers syndrome. J. Med. Genet. 42: 428-435, 2005. [PubMed: 15863673] [Full Text: https://doi.org/10.1136/jmg.2004.026294]
Scott, R. J., Crooks, R., Meldrum, C. J., Thomas, L., Smith, C. J. A., Mowat, D., McPhillips, M., Spigelman, A. D. Mutation analysis of the STK11/LKB1 gene and clinical characteristics of an Australian series of Peutz-Jeghers syndrome patients. Clin. Genet. 62: 282-287, 2002. [PubMed: 12372054] [Full Text: https://doi.org/10.1034/j.1399-0004.2002.620405.x]
Shaw, R. J., Lamia, K. A., Vasquez, D., Koo, S.-H., Bardeesy, N., DePinho, R. A., Montminy, M., Cantley, L. C. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310: 1642-1646, 2005. [PubMed: 16308421] [Full Text: https://doi.org/10.1126/science.1120781]
Shinmura, K., Goto, M., Tao, H., Shimizu, S., Otsuki, Y., Kobayashi, H., Ushida, S., Suzuki, K., Tsuneyoshi, T., Sugimura, H. A novel STK11 germline mutation in two siblings with Peutz-Jeghers syndrome complicated by primary gastric cancer. Clin. Genet. 67: 81-86, 2005. [PubMed: 15617552] [Full Text: https://doi.org/10.1111/j.1399-0004.2005.00380.x]
Smith, D. P., Rayter, S. I., Niederlander, C., Spicer, J., Jones, C. M., Ashworth, A. LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1. Hum. Molec. Genet. 10: 2869-2877, 2001. [PubMed: 11741830] [Full Text: https://doi.org/10.1093/hmg/10.25.2869]
Smith, D. P., Spicer, J., Smith, A., Swift, S., Ashworth, A. The mouse Peutz-Jeghers syndrome gene Lkb1 encodes a nuclear protein kinase. Hum. Molec. Genet. 8: 1479-1485, 1999. [PubMed: 10400995] [Full Text: https://doi.org/10.1093/hmg/8.8.1479]
Su, G. H., Hruban, R. H., Bansal, R. K., Bova, G. S., Tang, D. J., Shekher, M. C., Westerman, A. M., Entius, M. M., Goggins, M., Yeo, C. J., Kern, S. E. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am. J. Path. 154: 1835-1840, 1999. [PubMed: 10362809] [Full Text: https://doi.org/10.1016/S0002-9440(10)65440-5]
Su, J.-Y., Erikson, E., Maller, J. L. Cloning and characterization of a novel serine/threonine protein kinase expressed in early Xenopus embryos. J. Biol. Chem. 271: 14430-14437, 1996. [PubMed: 8662877] [Full Text: https://doi.org/10.1074/jbc.271.24.14430]
Tiainen, M., Vaahtomeri, K., Ylikorkala, Y., Makela, T. P. Growth arrest by the LKBI tumor suppressor: induction of p21(WAF1/CIP1). Hum. Molec. Genet. 11: 1497-1504, 2002. [PubMed: 12045203] [Full Text: https://doi.org/10.1093/hmg/11.13.1497]
Wang, Z.-J., Churchman, M., Campbell I. G., Xu, W.-H., Yan, Z.-Y., McCluggage, W. G., Foulkes, W. D., Tomlinson, I. P. M. Allele loss and mutation screen at the Peutz-Jeghers (LKB1) locus (19p13.3) in sporadic ovarian tumors. Brit. J. Cancer 80: 70-72, 1999. [PubMed: 10389980] [Full Text: https://doi.org/10.1038/sj.bjc.6690323]
Westerman, A. M., Entius, M. M., Boor, P. P. C., Koole, R., de Baar, E., Offerhaus, G. J. A., Lubinski, J., Lindhout, D., Halley, D. J. J., de Rooij, F. W. M., Wilson, J. H. P. Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers families. Hum. Mutat. 13: 476-481, 1999. [PubMed: 10408777] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)13:6<476::AID-HUMU7>3.0.CO;2-2]
Westerman, A. M., Entius, M. M., de Baar, E., Boor, P. P. C., Koole, R., van Velthuysen, M. L. F., Offerhaus, G. J. A., Lindhout, D., de Rooij, F. W. M., Wilson, J. H. P. Peutz-Jeghers syndrome: 78-year follow-up of the original family. Lancet 353: 1211-1215, 1999. [PubMed: 10217080] [Full Text: https://doi.org/10.1016/s0140-6736(98)08018-0]
Xu, X., Jin, D., Durgan, J., Hall, A. LKB1 controls human bronchial epithelial morphogenesis through p114RhoGEF-dependent RhoA activation. Molec. Cell. Biol. 33: 2671-2682, 2013. [PubMed: 23648482] [Full Text: https://doi.org/10.1128/MCB.00154-13]
Yang, K., Blanco, D. B., Neale, G., Vogel, P., Avila, J., Clish, C. B., Wu, C., Shrestha, S., Rankin, S., Long, L., KC, A., Chi, H. Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling. Nature 548: 602-606, 2017. [PubMed: 28847007] [Full Text: https://doi.org/10.1038/nature23665]
Ylikorkala, A., Avizienyte, E., Tomlinson, I. P. M., Tiainen, M., Roth, S., Loukola, A., Hemminki, A., Johansson, M., Sistonen, P., Markie, D., Neale, K., Phillips, R., Zauber, P., Twama, T., Sampson, J., Jarvinen, H., Makela, T. P., Aaltonen, L. A. Mutations and impaired function of LKB1 in familial and non-familial Peutz-Jeghers syndrome and a sporadic testicular cancer. Hum. Molec. Genet. 8: 45-51, 1999. [PubMed: 9887330] [Full Text: https://doi.org/10.1093/hmg/8.1.45]
Ylikorkala, A., Rossi, D. J., Korsisaari, N., Luukko, K., Alitalo, K., Henkemeyer, M., Makela, T. P. Vascular abnormalities and deregulation of VEGF in Lkb-1-deficient mice. Science 293: 1323-1326, 2001. [PubMed: 11509733] [Full Text: https://doi.org/10.1126/science.1062074]
Zeqiraj, E., Filippi, B. M., Deak, M., Alessi, D. R., van Aalten, D. M. F. Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. Science 326: 1707-1711, 2009. [PubMed: 19892943] [Full Text: https://doi.org/10.1126/science.1178377]