cyclin-dependent protein kinase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   3 VSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSP-PDEVIQTICSANTLQFVQS 81
Cdd:PTZ00024 194 VVTLWYRAPELLMGAEKYHFAVDMWSVGCIFAELLTGKPLFPGENEIDQLGRIFELLGTPnEDNWPQAKKLPLYTEFTPR 273

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322  82 LPKRerqpLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEYLAPYH---DPTDEP 138
Cdd:PTZ00024 274 KPKD----LKTIFPNASDDAIDLLQSLLKLNPLERISAKEALKHEYFKSDPlpcDPSQLP 329

Protein kinase domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322    2 YVSTRYYRAPEImLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITellgsppdeviqticsantlqfvqs 81
Cdd:pfam00069 120 FVGTPWYMAPEV-LGGNPYGPKVDVWSLGCILYELLTGKPPFPGINGNEIYELII------------------------- 173

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 478786322   82 lpkRERQPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEYL 128
Cdd:pfam00069 174 ---DQPYAFPELPSNLSEEAKDLLKKLLKKDPSKRLTATQALQHPWF 217

Catalytic domain of the Serine/Threonine Kinase, Mitogen-Activated Protein Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MAPKs serve as important mediators of cellular responses to extracellular signals. They control critical cellular functions including differentiation, proliferation, migration, and apoptosis. They are also implicated in the pathogenesis of many diseases including multiple types of cancer, stroke, diabetes, and chronic inflammation. Typical MAPK pathways involve a triple kinase core cascade comprising of the MAPK, which is phosphorylated and activated by a MAPK kinase (MAP2K or MKK), which itself is phosphorylated and activated by a MAPK kinase kinase (MAP3K or MKKK). Each cascade is activated either by a small GTP-binding protein or by an adaptor protein, which transmits the signal either directly to a MAP3K to start the triple kinase core cascade or indirectly through a mediator kinase, a MAP4K. There are three typical MAPK subfamilies: Extracellular signal-Regulated Kinase (ERK), c-Jun N-terminal Kinase (JNK), and p38. Some MAPKs are atypical in that they are not regulated by MAP2Ks. These include MAPK4, MAPK6, NLK, and ERK7. The MAPK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   1 GYVSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTICSANTLQFVQ 80
Cdd:cd07834  164 EYVVTRWYRAPELLLSSKKYTKAIDIWSVGCIFAELLTRKPLFPGRDYIDQLNLIVEVLGTPSEEDLKFISSEKARNYLK 243

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322  81 SLPKRERQPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEYLAPYHDPTDEPIAEEKFDWSFND 150
Cdd:cd07834  244 SLPKKPKKPLSEVFPGASPEAIDLLEKMLVFNPKKRITADEALAHPYLAQLHDPEDEPVAKPPFDFPFFD 313

Catalytic domain of Extracellular signal-Regulated Kinase 1 and 2-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of the mitogen-activated protein kinases (MAPKs) ERK1, ERK2, baker's yeast Fus3, and similar proteins. MAPK pathways are important mediators of cellular responses to extracellular signals. ERK1/2 activation is preferentially by mitogenic factors, differentiation stimuli, and cytokines, through a kinase cascade involving the MAPK kinases MEK1/2 and a MAPK kinase kinase from the Raf family. ERK1/2 have numerous substrates, many of which are nuclear and participate in transcriptional regulation of many cellular processes. They regulate cell growth, cell proliferation, and cell cycle progression from G1 to S phase. Although the distinct roles of ERK1 and ERK2 have not been fully determined, it is known that ERK2 can maintain most functions in the absence of ERK1, and that the deletion of ERK2 is embryonically lethal. The MAPK, Fus3, regulates yeast mating processes including mating-specific gene expression, G1 arrest, mating projection, and cell fusion. This ERK1/2-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   2 YVSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTICSANTLQFVQS 81
Cdd:cd07849  169 YVATRWYRAPEIMLNSKGYTKAIDIWSVGCILAEMLSNRPLFPGKDYLHQLNLILGILGTPSQEDLNCIISLKARNYIKS 248

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 478786322  82 LPKRERQPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEYLAPYHDPTDEPIAEEKFDWSFND 150
Cdd:cd07849  249 LPFKPKVPWNKLFPNADPKALDLLDKMLTFNPHKRITVEEALAHPYLEQYHDPSDEPVAEEPFPFDMEL 317

Catalytic domain of the Serine/Threonine Kinase, p38alpha Mitogen-Activated Protein Kinase (also called MAPK14); STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. p38alpha/MAPK14 is expressed in most tissues and is the major isoform involved in the immune and inflammatory response. It is the central p38 MAPK involved in myogenesis. It plays a role in regulating cell cycle check-point transition and promoting cell differentiation. p38alpha also regulates cell proliferation and death through crosstalk with the JNK pathway. Its substrates include MAPK activated protein kinase 2 (MK2), MK5, and the transcription factors ATF2 and Mitf. p38 kinases MAPKs, serving as important mediators of cellular responses to extracellular signals. They are activated by the MAPK kinases MKK3 and MKK6, which in turn are activated by upstream MAPK kinase kinases including TAK1, ASK1, and MLK3, in response to cellular stresses or inflammatory cytokines. The p38alpha subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   1 GYVSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTICSANTLQFVQ 80
Cdd:cd07877  176 GYVATRWYRAPEIMLNWMHYNQTVDIWSVGCIMAELLTGRTLFPGTDHIDQLKLILRLVGTPGAELLKKISSESARNYIQ 255

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 478786322  81 SLPKRERQPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEYLAPYHDPTDEPIAeEKFDWSF 148
Cdd:cd07877  256 SLTQMPKMNFANVFIGANPLAVDLLEKMLVLDSDKRITAAQALAHAYFAQYHDPDDEPVA-DPYDQSF 322

Catalytic domain of the Serine/Threonine Kinase, p38beta Mitogen-Activated Protein Kinase (also called MAPK11); STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. p38beta/MAPK11 is widely expressed in tissues and shows more similarity with p38alpha than with the other isoforms. Both are sensitive to pyridinylimidazoles and share some common substrates such as MAPK activated protein kinase 2 (MK2) and the transcription factors ATF2, c-Fos and, ELK-1. p38beta is involved in regulating the activation of the cyclooxygenase-2 promoter and the expression of TGFbeta-induced alpha-smooth muscle cell actin. p38 kinases are mitogen-activated protein kinases (MAPKs), serving as important mediators of cellular responses to extracellular signals. They are activated by the MAPK kinases MKK3 and MKK6, which in turn are activated by upstream MAPK kinase kinases including TAK1, ASK1, and MLK3, in response to cellular stresses or inflammatory cytokines. The p38beta subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   1 GYVSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTICSANTLQFVQ 80
Cdd:cd07878  174 GYVATRWYRAPEIMLNWMHYNQTVDIWSVGCIMAELLKGKALFPGNDYIDQLKRIMEVVGTPSPEVLKKISSEHARKYIQ 253

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 478786322  81 SLPKRERQPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEYLAPYHDPTDEPIAE 141
Cdd:cd07878  254 SLPHMPQQDLKKIFRGANPLAIDLLEKMLVLDSDKRISASEALAHPYFSQYHDPEDEPEAE 314

Catalytic domain of the Serine/Threonine Kinase, Mitogen-Activated Protein Kinase 15 and similar MAPKs; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Human MAPK15 is also called Extracellular signal Regulated Kinase 8 (ERK8) while the rat protein is called ERK7. ERK7 and ERK8 display both similar and different biochemical properties. They autophosphorylate and activate themselves and do not require upstream activating kinases. ERK7 is constitutively active and is not affected by extracellular stimuli whereas ERK8 shows low basal activity and is activated by DNA-damaging agents. ERK7 and ERK8 also have different substrate profiles. Genome analysis shows that they are orthologs with similar gene structures. ERK7 and ERK 8 may be involved in the signaling of some nuclear receptor transcription factors. ERK7 regulates hormone-dependent degradation of estrogen receptor alpha while ERK8 down-regulates the transcriptional co-activation androgen and glucocorticoid receptors. MAPKs are important mediators of cellular responses to extracellular signals. The MAPK15 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   2 YVSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTICSANTLQFVQS 81
Cdd:cd07852  172 YVATRWYRAPEILLGSTRYTKGVDMWSVGCILGEMLLGKPLFPGTSTLNQLEKIIEVIGRPSAEDIESIQSPFAATMLES 251

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 478786322  82 LPKRERQPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEYLAPYHDPTDEPIAEEKFDWSFND 150
Cdd:cd07852  252 LPPSRPKSLDELFPKASPDALDLLKKLLVFNPNKRLTAEEALRHPYVAQFHNPADEPSLPGPIVIPLDD 320

Catalytic domain of the Serine/Threonine Kinases, Plant TDY Mitogen-Activated Protein Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Plant MAPKs are typed based on the conserved phosphorylation motif present in the activation loop, TEY and TDY. This subfamily represents the TDY subtype and is composed of Group D plant MAPKs including Arabidopsis thaliana MPK18 (AtMPK18), Oryza sativa Blast- and Wound-induced MAPK1 (OsBWMK1), OsWJUMK1 (Wound- and JA-Uninducible MAPK1), Zea mays MPK6, and the Medicago sativa TDY1 gene product. OsBWMK1 enhances resistance to pathogenic infections. It mediates stress-activated defense responses by activating a transcription factor that affects the expression of stress-related genes. AtMPK18 is involved in microtubule-related functions. In plants, MAPKs are associated with physiological, developmental, hormonal, and stress responses. Some plants show numerous gene duplications of MAPKs; Arabidopsis thaliana harbors at least 20 MAPKs, named AtMPK1-20 while Oryza sativa contains at least 17 MAPKs. Arabidopsis thaliana contains more TEY-type MAPKs than TDY-type, whereas the reverse is true for Oryza sativa. The TDY MAPK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   2 YVSTRYYRAPEIMLT-WQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTICSANTLQFVQ 80
Cdd:cd07859  166 YVATRWYRAPELCGSfFSKYTPAIDIWSIGCIFAEVLTGKPLFPGKNVVHQLDLITDLLGTPSPETISRVRNEKARRYLS 245

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322  81 SLPKRERQPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEYLAPY----HDPTDEPIAEEKFDW 146
Cdd:cd07859  246 SMRKKQPVPFSQKFPNADPLALRLLERLLAFDPKDRPTAEEALADPYFKGLakveREPSAQPITKLEFEF 315

The catalytic domain of the Serine/Threonine Kinase, Glycogen Synthase Kinase 3; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. GSK3 is a mutifunctional kinase involved in many cellular processes including cell division, proliferation, differentiation, adhesion, and apoptosis. In plants, GSK3 plays a role in the response to osmotic stress. In Caenorhabditis elegans, it plays a role in regulating normal oocyte-to-embryo transition and response to oxidative stress. In Chlamydomonas reinhardtii, GSK3 regulates flagellar length and assembly. In mammals, there are two isoforms, GSK3alpha and GSK3beta, which show both distinct and redundant functions. The two isoforms differ mainly in their N-termini. They are both involved in axon formation and in Wnt signaling.They play distinct roles in cardiogenesis, with GSKalpha being essential in cardiomyocyte survival, and GSKbeta regulating heart positioning and left-right symmetry. GSK3beta was first identified as a regulator of glycogen synthesis, but has since been determined to play other roles. It regulates the degradation of beta-catenin and IkB. Beta-catenin is the main effector of Wnt, which is involved in normal haematopoiesis and stem cell function. IkB is a central inhibitor of NF-kB, which is critical in maintaining leukemic cell growth. GSK3beta is enriched in the brain and is involved in regulating neuronal signaling pathways. It is implicated in the pathogenesis of many diseases including Type II diabetes, obesity, mood disorders, Alzheimer's disease, osteoporosis, and some types of cancer, among others. The GSK3 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   2 YVSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTICSANTLqfvQS 81
Cdd:cd14137  166 YICSRYYRAPELIFGATDYTTAIDIWSAGCVLAELLLGQPLFPGESSVDQLVEIIKVLGTPTREQIKAMNPNYTE---FK 242

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 478786322  82 LPKRERQPLSDKF-KDADPLAVDLLERMLVFDPKQRISAADGLAHeylaPYHD 133
Cdd:cd14137  243 FPQIKPHPWEKVFpKRTPPDAIDLLSKILVYNPSKRLTALEALAH----PFFD 291

Catalytic domain of Cyclin-Dependent protein Kinase 9-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of CDK9 and CDK12 from higher eukaryotes, yeast BUR1, C-type plant CDKs (CdkC), and similar proteins. CDK9, BUR1, and CdkC are functionally equivalent. They act as a kinase for the C-terminal domain of RNA polymerase II and participate in regulating mutliple steps of gene expression including transcription elongation and RNA processing. CDK9 and CdkC associate with T-type cyclins while BUR1 associates with the cyclin BUR2. CDK12 is a unique CDK that contains an arginine/serine-rich (RS) domain, which is predominantly found in splicing factors. CDK12 interacts with cyclins L1 and L2, and participates in regulating transcription and alternative splicing. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. The CDK9-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   3 VSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEV---IQTICSANTLQFV 79
Cdd:cd07840  166 VITLWYRPPELLLGATRYGPEVDMWSVGCILAELFTGKPIFQGKTELEQLEKIFELCGSPTEENwpgVSDLPWFENLKPK 245

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 478786322  80 QSLPKRERqplsDKFKDA-DPLAVDLLERMLVFDPKQRISAADGLAHEY 127
Cdd:cd07840  246 KPYKRRLR----EVFKNViDPSALDLLDKLLTLDPKKRISADQALQHEY 290

Catalytic domain of the Serine/Threonine Kinase, c-Jun N-terminal Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. JNKs are mitogen-activated protein kinases (MAPKs) that are involved in many stress-activated responses including those during inflammation, neurodegeneration, apoptosis, and persistent pain sensitization, among others. They are also essential regulators of physiological and pathological processes and are involved in the pathogenesis of several diseases such as diabetes, atherosclerosis, stroke, Parkinson's and Alzheimer's. Vetebrates harbor three different JNK genes (Jnk1, Jnk2, and Jnk3) that are alternatively spliced to produce at least 10 isoforms. JNKs are specifically activated by the MAPK kinases MKK4 and MKK7, which are in turn activated by upstream MAPK kinase kinases as a result of different stimuli including stresses such as ultraviolet (UV) irradiation, hyperosmolarity, heat shock, or cytokines. JNKs activate a large number of different substrates based on specific stimulus, cell type, and cellular condition, and may be implicated in seemingly contradictory functions. The JNK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   2 YVSTRYYRAPEIMLTwQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTICSAnTLQFVQS 81
Cdd:cd07850  161 YVVTRYYRAPEVILG-MGYKENVDIWSVGCIMGEMIRGTVLFPGTDHIDQWNKIIEQLGTPSDEFMSRLQPT-VRNYVEN 238

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322  82 LPKRERQPLSDKFKDA---------DPL----AVDLLERMLVFDPKQRISAADGLAHEYLAPYHDPTD-EPIAEEKFDWS 147
Cdd:cd07850  239 RPKYAGYSFEELFPDVlfppdseehNKLkasqARDLLSKMLVIDPEKRISVDDALQHPYINVWYDPSEvEAPPPAPYDHS 318

                 ....
gi 478786322 148 FNDA 151
Cdd:cd07850  319 IDER 322

Catalytic domain of the Serine/Threonine Kinase, MAPK/MAK/MRK Overlapping Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MOK, also called Renal tumor antigen 1 (RAGE-1), is widely expressed and is enriched in testis, kidney, lung, and brain. It is expressed in approximately 50% of renal cell carcinomas (RCC) and is a potential target for immunotherapy. MOK is stabilized by its association with the HSP90 molecular chaperone. It is induced by the transcription factor Cdx2 and may be involved in regulating intestinal epithelial development and differentiation. The MOK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   2 YVSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTICSANTLQFvqS 81
Cdd:cd07831  158 YISTRWYRAPECLLTDGYYGPKMDIWAVGCVFFEILSLFPLFPGTNELDQIAKIHDVLGTPDAEVLKKFRKSRHMNY--N 235

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 478786322  82 LPKRERQPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEY 127
Cdd:cd07831  236 FPSKKGTGLRKLLPNASAEGLDLLKKLLAYDPDERITAKQALRHPY 281

Catalytic domain of Cyclin-Dependent protein Kinase 1-like Serine/Threonine Kinases and of Plant B-type Cyclin-Dependent protein Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of CDK, CDK2, and CDK3. CDK1 is also called Cell division control protein 2 (Cdc2) or p34 protein kinase, and is regulated by cyclins A, B, and E. The CDK1/cyclin A complex controls G2 phase entry and progression while the CDK1/cyclin B complex is critical for G2 to M phase transition. CDK2 is regulated by cyclin E or cyclin A. Upon activation by cyclin E, it phosphorylates the retinoblastoma (pRb) protein which activates E2F mediated transcription and allows cells to move into S phase. The CDK2/cyclin A complex plays a role in regulating DNA replication. Studies in knockout mice revealed that CDK1 can compensate for the loss of the cdk2 gene as it can also bind cyclin E and drive G1 to S phase transition. CDK3 is regulated by cyclin C and it phosphorylates pRB specifically during the G0/G1 transition. This phosphorylation is required for cells to exit G0 efficiently and enter the G1 phase. The plant-specific B-type CDKs are expressed from the late S to the M phase of the cell cycle. They are characterized by the cyclin binding motif PPT[A/T]LRE. They play a role in controlling mitosis and integrating developmental pathways, such as stomata and leaf development. CdkB has been shown to associate with both cyclin B, which controls G2/M transition, and cyclin D, which acts as a mediator in linking extracellular signals to the cell cycle. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. The CDK1 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   3 VSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTICSAntLQFVQSL 82
Cdd:cd07835  160 VVTLWYRAPEILLGSKHYSTPVDIWSVGCIFAEMVTRRPLFPGDSEIDQLFRIFRTLGTPDEDVWPGVTSL--PDYKPTF 237

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 478786322  83 PKRERQPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEYL 128
Cdd:cd07835  238 PKWARQDLSKVVPSLDEDGLDLLSQMLVYDPAKRISAKAALQHPYF 283

Catalytic domain of Cyclin-Dependent protein Kinase 4 and 6-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CDK4 and CDK6 partner with D-type cyclins to regulate the early G1 phase of the cell cycle. They are the first kinases activated by mitogenic signals to release cells from the G0 arrested state. CDK4 and CDK6 are both expressed ubiquitously, associate with all three D cyclins (D1, D2 and D3), and phosphorylate the retinoblastoma (pRb) protein. They are also regulated by the INK4 family of inhibitors which associate with either the CDK alone or the CDK/cyclin complex. CDK4 and CDK6 show differences in subcellular localization, sensitivity to some inhibitors, timing in activation, tumor selectivity, and possibly substrate profiles. Although CDK4 and CDK6 seem to show some redundancy, they also have discrete, nonoverlapping functions. CDK6 plays an important role in cell differentiation. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. The CDK4/6-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   3 VSTRYYRAPEIMLTwQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPdeviQTICSANTLQFVQSL 82
Cdd:cd07838  167 VVTLWYRAPEVLLQ-SSYATPVDMWSVGCIFAELFNRRPLFRGSSEADQLGKIFDVIGLPS----EEEWPRNSALPRSSF 241

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 478786322  83 PKRERQPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEYL 128
Cdd:cd07838  242 PSYTPRPFKSFVPEIDEEGLDLLKKMLTFNPHKRISAFEALQHPYF 287

Catalytic domain of the Serine/Threonine Kinase, Fungal Cyclin-Dependent protein Kinase Pho85; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Pho85 is a multifunctional CDK in yeast. It is regulated by 10 different cyclins (Pcls) and plays a role in G1 progression, cell polarity, phosphate and glycogen metabolism, gene expression, and in signaling changes in the environment. It is not essential for yeast viability and is the functional homolog of mammalian CDK5, which plays a role in central nervous system development. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. The Pho85 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   3 VSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTIcsANTLQFVQSL 82
Cdd:cd07836  161 VVTLWYRAPDVLLGSRTYSTSIDIWSVGCIMAEMITGRPLFPGTNNEDQLLKIFRIMGTPTESTWPGI--SQLPEYKPTF 238

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 478786322  83 PKRERQPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEY 127
Cdd:cd07836  239 PRYPPQDLQQLFPHADPLGIDLLHRLLQLNPELRISAHDALQHPW 283

Catalytic domain of the Serine/Threonine Kinase, Cyclin-Dependent protein Kinase 7; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CDK7 plays essential roles in the cell cycle and in transcription. It associates with cyclin H and MAT1 and acts as a CDK-Activating Kinase (CAK) by phosphorylating and activating cell cycle CDKs (CDK1/2/4/6). In the brain, it activates CDK5. CDK7 is also a component of the general transcription factor TFIIH, which phosphorylates the C-terminal domain (CTD) of RNA polymerase II when it is bound with unphosphorylated DNA, as present in the pre-initiation complex. Following phosphorylation, the CTD dissociates from the DNA which allows transcription initiation. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. The CDK7 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   3 VSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTICS-ANTLQFVQS 81
Cdd:cd07841  163 VVTRWYRAPELLFGARHYGVGVDMWSVGCIFAELLLRVPFLPGDSDIDQLGKIFEALGTPTEENWPGVTSlPDYVEFKPF 242

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 478786322  82 LPKrerqPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEYLAPYHDPTDEP 138
Cdd:cd07841  243 PPT----PLKQIFPAASDDALDLLQRLLTLNPNKRITARQALEHPYFSNDPAPTPPS 295

Catalytic domain of the Serine/Threonine Kinase, Fungal Cyclin-Dependent protein Kinase (CDK), Bypass UAS Requirement 1, and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. BUR1, also called SGV1, is a yeast CDK that is functionally equivalent to mammalian CDK9. It associates with the cyclin BUR2. BUR genes were orginally identified in a genetic screen as factors involved in general transcription. The BUR1/BUR2 complex phosphorylates the C-terminal domain of RNA polymerase II. In addition, this complex regulates histone modification by phosporylating Rad6 and mediating the association of the Paf1 complex with chromatin. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. The BUR1 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   1 GYVSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEviqTICSANTLQFVQ 80
Cdd:cd07866  185 NLVVTRWYRPPELLLGERRYTTAVDIWGIGCVFAEMFTRRPILQGKSDIDQLHLIFKLCGTPTEE---TWPGWRSLPGCE 261

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 478786322  81 SLPKRERQP--LSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEY 127
Cdd:cd07866  262 GVHSFTNYPrtLEERFGKLGPEGLDLLSKLLSLDPYKRLTASDALEHPY 310

Catalytic domain of the Serine/Threonine Kinase, Cyclin-Dependent protein Kinase 1 from higher eukaryotes; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CDK1 is also called Cell division control protein 2 (Cdc2) or p34 protein kinase, and is regulated by cyclins A, B, and E. The CDK1/cyclin A complex controls G2 phase entry and progression. CDK1/cyclin A2 has also been implicated as an important regulator of S phase events. The CDK1/cyclin B complex is critical for G2 to M phase transition. It induces mitosis by activating nuclear enzymes that regulate chromatin condensation, nuclear membrane degradation, mitosis-specific microtubule and cytoskeletal reorganization. CDK1 also associates with cyclin E and plays a role in the entry into S phase. CDK1 transcription is stable throughout the cell cycle but is modulated in some pathological conditions. It may play a role in regulating apoptosis under these conditions. In breast cancer cells, HER2 can mediate apoptosis by inactivating CDK1. Activation of CDK1 may contribute to HIV-1 induced apoptosis as well as neuronal apoptosis in neurodegenerative diseases. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. The CDK1 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   3 VSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTICSantLQ-FVQS 81
Cdd:cd07861  162 VVTLWYRAPEVLLGSPRYSTPVDIWSIGTIFAEMATKKPLFHGDSEIDQLFRIFRILGTPTEDIWPGVTS---LPdYKNT 238

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 478786322  82 LPKRERQPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEYL 128
Cdd:cd07861  239 FPKWKKGSLRTAVKNLDEDGLDLLEKMLIYDPAKRISAKKALVHPYF 285

Catalytic domain of the Serine/Threonine Kinases, Cyclin-Dependent protein Kinase 2 and 3; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CDK2 is regulated by cyclin E or cyclin A. Upon activation by cyclin E, it phosphorylates the retinoblastoma (pRb) protein which activates E2F mediated transcription and allows cells to move into S phase. The CDK2/cyclin A complex plays a role in regulating DNA replication. CDK2, together with CDK4, also regulates embryonic cell proliferation. Despite these important roles, mice deleted for the cdk2 gene are viable and normal except for being sterile. This may be due to compensation provided by CDK1 (also called Cdc2), which can also bind cyclin E and drive the G1 to S phase transition. CDK3 is regulated by cyclin C and it phosphorylates pRB specifically during the G0/G1 transition. This phosphorylation is required for cells to exit G0 efficiently and enter the G1 phase. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. The CDK2/3 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   3 VSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTICSANtlQFVQSL 82
Cdd:cd07860  161 VVTLWYRAPEILLGCKYYSTAVDIWSLGCIFAEMVTRRALFPGDSEIDQLFRIFRTLGTPDEVVWPGVTSMP--DYKPSF 238

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 478786322  83 PKRERQPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEY 127
Cdd:cd07860  239 PKWARQDFSKVVPPLDEDGRDLLSQMLHYDPNKRISAKAALAHPF 283

Catalytic domain of Cyclin-Dependent protein Kinase Like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of CDKL1-5 and similar proteins. Some CDKLs, like CDKL1 and CDKL3, may be implicated in transformation and others, like CDKL3 and CDKL5, are associated with mental retardation when impaired. CDKL2 plays a role in learning and memory. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. The CDKL subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   2 YVSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTICSANTLQFVQS 81
Cdd:cd07833  161 YVATRWYRAPELLVGDTNYGKPVDVWAIGCIMAELLDGEPLFPGDSDIDQLYLIQKCLGPLPPSHQELFSSNPRFAGVAF 240

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 478786322  82 LPKRERQPLSDKF-KDADPLAVDLLERMLVFDPKQRISAADGLAHEYL 128
Cdd:cd07833  241 PEPSQPESLERRYpGKVSSPALDFLKACLRMDPKERLTCDELLQHPYF 288

Catalytic domain of the Serine/Threonine Kinase, Plant B-type Cyclin-Dependent protein Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The plant-specific B-type CDKs are expressed from the late S to the M phase of the cell cycle. They are characterized by the cyclin binding motif PPT[A/T]LRE. They play a role in controlling mitosis and integrating developmental pathways, such as stomata and leaf development. CdkB has been shown to associate with both cyclin B, which controls G2/M transition, and cyclin D, which acts as a mediator in linking extracellular signals to the cell cycle. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. The CdkB subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   5 TRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTIcsaNTLQFVQSLPK 84
Cdd:cd07837  173 TLWYRAPEVLLGSTHYSTPVDMWSVGCIFAEMSRKQPLFPGDSELQQLLHIFRLLGTPNEEVWPGV---SKLRDWHEYPQ 249

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 478786322  85 RERQPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEY 127
Cdd:cd07837  250 WKPQDLSRAVPDLEPEGVDLLTKMLAYDPAKRISAKAALQHPY 292

Catalytic domain of the Serine/Threonine Kinase, Cyclin-Dependent protein Kinase 10; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CDK10, also called PISSLRE, is essential for cell growth and proliferation, and acts through the G2/M phase of the cell cycle. CDK10 has also been identified as an important factor in endocrine therapy resistance in breast cancer. CDK10 silencing increases the transcription of c-RAF and the activation of the p42/p44 MAPK pathway, which leads to antiestrogen resistance. Patients who express low levels of CDK10 relapse early on tamoxifen. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. The CDK10 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 478786322   3 VSTRYYRAPEIMLTWQKYDVEVDVWSAGCIFAEMLSGKPLFPGKDHVNQFSIITELLGSPPDEVIQTICSantLQFVQ-- 80
Cdd:cd07845  169 VVTLWYRAPELLLGCTTYTTAIDMWAVGCILAELLAHKPLLPGKSEIEQLDLIIQLLGTPNESIWPGFSD---LPLVGkf 245

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 478786322  81 SLPKRERQPLSDKFKDADPLAVDLLERMLVFDPKQRISAADGLAHEYL--APYH-DPTDEP 138
Cdd:cd07845  246 TLPKQPYNNLKHKFPWLSEAGLRLLNFLLMYDPKKRATAEEALESSYFkeKPLPcEPEMMP 306