PB1 domain is essential part of the mitogen-activated protein kinase kinase 5 (Map2k5, alias MEK5) one of the key member of the signaling kinases cascade which involved in angiogenesis and early cardiovascular development. The PB1 domain of Map2k5 interacts with the PB1 domain of another members of kinase cascade MEKK2 (or MEKK3). A canonical PB1-PB1 interaction, involving heterodimerization of two PB1 domain, is required for the formation of macromolecular signaling complexes ensuring specificity and fidelity during cellular signaling. The interaction between two PB1 domain depends on the type of PB1. There are three types of PB1 domains: type I which contains an OPCA motif, acidic aminoacid cluster, type II which contains a basic cluster, and type I/II which contains both an OPCA motif and a basic cluster. The Map2k5 protein contains a type I PB1 domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984716  17 LVIRIKIPNSGAVDWTVHSGPQLLFRDVLDVIGQVLPEATTTAFEYEDEDGDRITVRSDEEMKAMLSYYYSTVMEQQVNG 96
Cdd:cd06395    1 LVIRIKIPNGGAVDWTVQSGPQLLFRDVLDVIGQVLPEATTTAFEYEDEDGDRITVRSDEEMKAMLSYYCSTVMEQQVNG 80

                         90
                 ....*....|.
gi 767984716  97 QLIEPLQIFPR 107
Cdd:cd06395   81 QLIEPLQIFPR 91

PB1 domain is essential part of the mitogen-activated protein kinase kinase 5 (Map2k5, alias MEK5) one of the key member of the signaling kinases cascade which involved in angiogenesis and early cardiovascular development. The PB1 domain of Map2k5 interacts with the PB1 domain of another members of kinase cascade MEKK2 (or MEKK3). A canonical PB1-PB1 interaction, involving heterodimerization of two PB1 domain, is required for the formation of macromolecular signaling complexes ensuring specificity and fidelity during cellular signaling. The interaction between two PB1 domain depends on the type of PB1. There are three types of PB1 domains: type I which contains an OPCA motif, acidic aminoacid cluster, type II which contains a basic cluster, and type I/II which contains both an OPCA motif and a basic cluster. The Map2k5 protein contains a type I PB1 domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984716  17 LVIRIKIPNSGAVDWTVHSGPQLLFRDVLDVIGQVLPEATTTAFEYEDEDGDRITVRSDEEMKAMLSYYYSTVMEQQVNG 96
Cdd:cd06395    1 LVIRIKIPNGGAVDWTVQSGPQLLFRDVLDVIGQVLPEATTTAFEYEDEDGDRITVRSDEEMKAMLSYYCSTVMEQQVNG 80

                         90
                 ....*....|.
gi 767984716  97 QLIEPLQIFPR 107
Cdd:cd06395   81 QLIEPLQIFPR 91

Protein kinase domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984716  171 TLGHGNGGTVYKAYHVPSGKILAVKVILLD-ITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICTEFMDGGSL 249
Cdd:pfam00069   6 KLGSGSFGTVYKAKHRDTGKIVAIKKIKKEkIKKKKDKNILREIKILKKLNHPNIVRLYDAFEDKDNLYLVLEYVEGGSL 85

                          90       100
                  ....*....|....*....|....*.
gi 767984716  250 D----VYRKMPEHVLGRIAVAVVKGL 271
Cdd:pfam00069  86 FdllsEKGAFSEREAKFIMKQILEGL 111

Serine/threonine protein kinase [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984716 161 MNEQDI-RYR--DTLGHGNGGTVYKAYHVPSGKILAVKVILLDITL--ELQKQIMSELEILYKCDSSYIIGFYGAFFVEN 235
Cdd:COG0515    1 MSALLLgRYRilRLLGRGGMGVVYLARDLRLGRPVALKVLRPELAAdpEARERFRREARALARLNHPNIVRVYDVGEEDG 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 767984716 236 RISICTEFMDGGSLDVY----RKMPEHVLGRIAVAVVKGLTYLWSLKILHR 282
Cdd:COG0515   81 RPYLVMEYVEGESLADLlrrrGPLPPAEALRILAQLAEALAAAHAAGIVHR 131

PB1 domain; Phox and Bem1p domain, present in many eukaryotic cytoplasmic signalling proteins. The domain adopts a beta-grasp fold, similar to that found in ubiquitin and Ras-binding domains. A motif, variously termed OPR, PC and AID, represents the most conserved region of the majority of PB1 domains, and is necessary for PB1 domain function. This function is the formation of PB1 domain heterodimers, although not all PB1 domain pairs associate.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 767984716    27 GAVDWTVHSGPQLLFRDVLDVIGQVLP-EATTTAFEYEDEDGDRITVRSDEEMKAMLSYYYST 88
Cdd:smart00666   9 GGETRRLSVPRDISFEDLRSKVAKRFGlDNQSFTLKYQDEDGDLVSLTSDEDLEEAIEEYDSL 71

Catalytic domain of the dual-specificity Protein Kinase, Mitogen-Activated Protein Kinase Kinase; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine (ST) or tyrosine residues on protein substrates. MAPKKs are dual-specificity PKs that phosphorylate their downstream targets, MAPKs, at specific threonine and tyrosine residues. The MAPK signaling pathways are important mediators of cellular responses to extracellular signals. The pathways involve a triple kinase core cascade comprising the MAPK, which is phosphorylated and activated by a MAPK kinase (MAPKK or MKK or MAP2K), which itself is phosphorylated and activated by a MAPKK kinase (MAPKKK or MKKK or MAP3K). There are three MAPK subfamilies: extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. In mammalian cells, there are seven MAPKKs (named MKK1-7) and 20 MAPKKKs. Each MAPK subfamily can be activated by at least two cognate MAPKKs and by multiple MAPKKKs. The MAPKK 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 767984716 164 QDIRYRDTLGHGNGGTVYKAYHVPSGKILAVKVILLDITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICTEF 243
Cdd:cd06605    1 DDLEYLGELGEGNGGVVSKVRHRPSGQIMAVKVIRLEIDEALQKQILRELDVLHKCNSPYIVGFYGAFYSEGDISICMEY 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 767984716 244 MDGGSLDVYRK----MPEHVLGRIAVAVVKGLTYLWS-LKILHR 282
Cdd:cd06605   81 MDGGSLDKILKevgrIPERILGKIAVAVVKGLIYLHEkHKIIHR 124

Catalytic domain of the dual-specificity Protein Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine (ST) or tyrosine residues on protein substrates. MEK1 and MEK2 are MAPK kinases (MAPKKs or MKKs), and are dual-specificity PKs that phosphorylate and activate the downstream targets, ERK1 and ERK2, on specific threonine and tyrosine residues. The ERK cascade starts with extracellular signals including growth factors, hormones, and neurotransmitters, which act through receptors and ion channels to initiate intracellular signaling that leads to the activation at the MAPKKK (Raf-1 or MOS) level, which leads to the transmission of signals to MEK1/2, and finally to ERK1/2. The ERK cascade plays an important role in cell proliferation, differentiation, oncogenic transformation, and cell cycle control, as well as in apoptosis and cell survival under certain conditions. This cascade has also been implicated in synaptic plasticity, migration, morphological determination, and stress response immunological reactions. Gain-of-function mutations in genes encoding ERK cascade proteins, including MEK1/2, cause cardiofaciocutaneous (CFC) syndrome, a condition leading to multiple congenital anomalies and mental retardation in patients. The MEK 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 767984716 172 LGHGNGGTVYKAYHVPSGKILAVKVILLDITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICTEFMDGGSLDV 251
Cdd:cd06615    9 LGAGNGGVVTKVLHRPSGLIMARKLIHLEIKPAIRNQIIRELKVLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQ 88

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 767984716 252 Y----RKMPEHVLGRIAVAVVKGLTYLWS-LKILHR 282
Cdd:cd06615   89 VlkkaGRIPENILGKISIAVLRGLTYLREkHKIMHR 124

Catalytic domain of Plant dual-specificity Mitogen-Activated Protein Kinase Kinases and similar proteins; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine (ST) or tyrosine residues on protein substrates. Members of this group include MAPKKs from plants, kinetoplastids, alveolates, and mycetozoa. The MAPKK, LmxPK4, from Leishmania mexicana, is important in differentiation and virulence. Dictyostelium discoideum MEK1 is required for proper chemotaxis; MEK1 null mutants display severe defects in cell polarization and directional movement. Plants contain multiple MAPKKs like other eukaryotes. The Arabidopsis genome encodes for 10 MAPKKs while poplar and rice contain 13 MAPKKs each. The functions of these proteins have not been fully elucidated. There is evidence to suggest that MAPK cascades are involved in plant stress responses. In Arabidopsis, MKK3 plays a role in pathogen signaling; MKK2 is involved in cold and salt stress signaling; MKK4/MKK5 participates in innate immunity; and MKK7 regulates basal and systemic acquired resistance. The MAPKK 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 767984716 165 DIRYRDTLGHGNGGTVYKAYHVPSGKILAVKVILLDITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICTEFM 244
Cdd:cd06623    2 DLERVKVLGQGSSGVVYKVRHKPTGKIYALKKIHVDGDEEFRKQLLRELKTLRSCESPYVVKCYGAFYKEGEISIVLEYM 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 767984716 245 DGGSLD----VYRKMPEHVLGRIAVAVVKGLTYLWS-LKILHR 282
Cdd:cd06623   82 DGGSLAdllkKVGKIPEPVLAYIARQILKGLDYLHTkRHIIHR 124

Catalytic domain of fungal Pek1-like dual-specificity Mitogen-Activated Protein Kinase Kinases; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine (ST) or tyrosine residues on protein substrates. Members of this group include the MAPKKs Pek1/Skh1 from Schizosaccharomyces pombe and MKK2 from Saccharomyces cerevisiae, and related proteins. Both fission yeast Pek1 and baker's yeast MKK2 are components of the cell integrity MAPK pathway. In fission yeast, Pek1 phosphorylates and activates Pmk1/Spm1 and is regulated by the MAPKK kinase Mkh1. In baker's yeast, the pathway involves the MAPK Slt2, the MAPKKs MKK1 and MKK2, and the MAPKK kinase Bck1. The cell integrity MAPK cascade is activated by multiple stress conditions, and is essential in cell wall construction, morphogenesis, cytokinesis, and ion homeostasis. MAPK signaling pathways are important mediators of cellular responses to extracellular signals. The MAPKK 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 767984716 166 IRYRDTLGHGNGGTVYKAYHVPSGKILAVKVILLDITLELQKQIMSELEILYKCDSSYIIGFYGAFFVE--NRISICTEF 243
Cdd:cd06621    3 IVELSSLGEGAGGSVTKCRLRNTKTIFALKTITTDPNPDVQKQILRELEINKSCASPYIVKYYGAFLDEqdSSIGIAMEY 82

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 767984716 244 MDGGSLD-VYRKM-------PEHVLGRIAVAVVKGLTYLWSLKILHR 282
Cdd:cd06621   83 CEGGSLDsIYKKVkkkggriGEKVLGKIAESVLKGLSYLHSRKIIHR 129

Catalytic domain of the dual-specificity Protein Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase 2; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine (ST) or tyrosine residues on protein substrates. MEK2 is a dual-specificity PK and a MAPK kinase (MAPKK or MKK) that phosphorylates and activates the downstream targets, ERK1 and ERK2, on specific threonine and tyrosine residues. The ERK cascade starts with extracellular signals including growth factors, hormones, and neurotransmitters, which act through receptors and ion channels to initiate intracellular signaling that leads to the activation at the MAPKKK (Raf-1 or MOS) level, which leads to the transmission of signals to MEK2, and finally to ERK1/2. The ERK cascade plays an important role in cell proliferation, differentiation, oncogenic transformation, and cell cycle control, as well as in apoptosis and cell survival under certain conditions. Gain-of-function mutations in genes encoding ERK cascade proteins, including MEK2, cause cardiofaciocutaneous (CFC) syndrome, a condition leading to multiple congenital anomalies and mental retardation in patients. The MEK subfamily is part of a larger superfamily that includes the catalytic domains of other protein serine/threonine kinases, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984716 160 QMNEQDIRYRDTLGHGNGGTVYKAYHVPSGKILAVKVILLDITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISI 239
Cdd:cd06649    1 ELKDDDFERISELGAGNGGVVTKVQHKPSGLIMARKLIHLEIKPAIRNQIIRELQVLHECNSPYIVGFYGAFYSDGEISI 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 767984716 240 CTEFMDGGSLDVY----RKMPEHVLGRIAVAVVKGLTYLWSL-KILHR 282
Cdd:cd06649   81 CMEHMDGGSLDQVlkeaKRIPEEILGKVSIAVLRGLAYLREKhQIMHR 128

Serine/Threonine protein kinases, catalytic domain; Phosphotransferases. Serine or threonine-specific kinase subfamily.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984716   170 DTLGHGNGGTVYKAYHVPSGKILAVKVILLDITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICTEFMDGGSL 249
Cdd:smart00220   5 EKLGEGSFGKVYLARDKKTGKLVAIKVIKKKKIKKDRERILREIKILKKLKHPNIVRLYDVFEDEDKLYLVMEYCEGGDL 84

                           90       100       110
                   ....*....|....*....|....*....|....*..
gi 767984716   250 ----DVYRKMPEHVLGRIAVAVVKGLTYLWSLKILHR 282
Cdd:smart00220  85 fdllKKRGRLSEDEARFYLRQILSALEYLHSKGIVHR 121

Catalytic domain of Protein Kinases; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine or tyrosine residues on protein substrates. PKs make up a large family of serine/threonine kinases (STKs), protein tyrosine kinases (PTKs), and dual-specificity PKs that phosphorylate both serine/threonine and tyrosine residues of target proteins. Majority of protein phosphorylation occurs on serine residues while only 1% occurs on tyrosine residues. Protein phosphorylation is a mechanism by which a wide variety of cellular proteins, such as enzymes and membrane channels, are reversibly regulated in response to certain stimuli. PKs often function as components of signal transduction pathways in which one kinase activates a second kinase, which in turn, may act on other kinases; this sequential action transmits a signal from the cell surface to target proteins, which results in cellular responses. The PK family is one of the largest known protein families with more than 100 homologous yeast enzymes and more than 500 human proteins. A fraction of PK family members are pseudokinases that lack crucial residues for catalytic activity. The mutiplicity of kinases allows for specific regulation according to substrate, tissue distribution, and cellular localization. PKs regulate many cellular processes including proliferation, division, differentiation, motility, survival, metabolism, cell-cycle progression, cytoskeletal rearrangement, immunity, and neuronal functions. Many kinases are implicated in the development of various human diseases including different types of cancer. The PK family is part of a larger superfamily that includes the catalytic domains of RIO kinases, aminoglycoside phosphotransferase, choline kinase, phosphoinositide 3-kinase (PI3K), and actin-fragmin kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984716 172 LGHGNGGTVYKAYHVPSGKILAVKVILLDITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICTEFMDGGSLDV 251
Cdd:cd00180    1 LGKGSFGKVYKARDKETGKKVAVKVIPKEKLKKLLEELLREIEILKKLNHPNIVKLYDVFETENFLYLVMEYCEGGSLKD 80

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 767984716 252 Y-----RKMPEHVLGRIAVAVVKGLTYLWSLKILHR 282
Cdd:cd00180   81 LlkenkGPLSEEEALSILRQLLSALEYLHSNGIIHR 116

Protein kinase domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984716  171 TLGHGNGGTVYKAYHVPSGKILAVKVILLD-ITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICTEFMDGGSL 249
Cdd:pfam00069   6 KLGSGSFGTVYKAKHRDTGKIVAIKKIKKEkIKKKKDKNILREIKILKKLNHPNIVRLYDAFEDKDNLYLVLEYVEGGSL 85

                          90       100
                  ....*....|....*....|....*.
gi 767984716  250 D----VYRKMPEHVLGRIAVAVVKGL 271
Cdd:pfam00069  86 FdllsEKGAFSEREAKFIMKQILEGL 111

Catalytic domain of Mitogen-activated protein kinase kinase kinase kinase (MAP4K) 3-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily includes MAP4K3, MAP4K1, MAP4K2, MAP4K5, and related proteins. Vertebrate members contain an N-terminal catalytic domain and a C-terminal citron homology (CNH) regulatory domain. MAP4K1, also called haematopoietic progenitor kinase 1 (HPK1), is a hematopoietic-specific STK involved in many cellular signaling cascades including MAPK, antigen receptor, apoptosis, growth factor, and cytokine signaling. It participates in the regulation of T cell receptor signaling and T cell-mediated immune responses. MAP4K2 was referred to as germinal center (GC) kinase because of its preferred location in GC B cells. MAP4K3 plays a role in the nutrient-responsive pathway of mTOR (mammalian target of rapamycin) signaling. It is required in the activation of S6 kinase by amino acids and for the phosphorylation of the mTOR-regulated inhibitor of eukaryotic initiation factor 4E. MAP4K5, also called germinal center kinase-related enzyme (GCKR), has been shown to activate the MAPK c-Jun N-terminal kinase (JNK). The MAP4K3-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 767984716 172 LGHGNGGTVYKAYHVPSGKILAVKVILLDITLELQkQIMSELEILYKCDSSYIIGFYGAFFVENRISICTEFMDGGSL-D 250
Cdd:cd06613    8 IGSGTYGDVYKARNIATGELAAVKVIKLEPGDDFE-IIQQEISMLKECRHPNIVAYFGSYLRRDKLWIVMEYCGGGSLqD 86

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 767984716 251 VY---RKMPEHVLGRIAVAVVKGLTYLWSLKILHR 282
Cdd:cd06613   87 IYqvtGPLSELQIAYVCRETLKGLAYLHSTGKIHR 121

Catalytic domain of the dual-specificity Protein Kinase, Mitogen-activated protein Kinase Kinase 7; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine (ST) or tyrosine residues on protein substrates. MKK7 is a dual-specificity PK that phosphorylates and activates its downstream target, c-Jun N-terminal kinase (JNK), on specific threonine and tyrosine residues. Although MKK7 is capable of dual phosphorylation, it prefers to phosphorylate the threonine residue of JNK. Thus, optimal activation of JNK requires both MKK4 and MKK7. MKK7 is primarily activated by cytokines. MKK7 is essential for liver formation during embryogenesis. It plays roles in G2/M cell cycle arrest and cell growth. In addition, it is involved in the control of programmed cell death, which is crucial in oncogenesis, cancer chemoresistance, and antagonism to TNFalpha-induced killing, through its inhibition by Gadd45beta and the subsequent suppression of the JNK cascade. The MKK7 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 767984716 172 LGHGNGGTVYKAYHVPSGKILAVKVILLDITLELQKQIMSELEILYKC-DSSYIIGFYGAFFVENRISICTEFMdGGSLD 250
Cdd:cd06618   23 IGSGTCGQVYKMRHKKTGHVMAVKQMRRSGNKEENKRILMDLDVVLKShDCPYIVKCYGYFITDSDVFICMELM-STCLD 101

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 767984716 251 -----VYRKMPEHVLGRIAVAVVKGLTYlwsLK----ILHR 282
Cdd:cd06618  102 kllkrIQGPIPEDILGKMTVSIVKALHY---LKekhgVIHR 139

Catalytic domain of Mammalian Ste20-like protein kinase 3-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 MST3, MST4, STK25, Schizosaccharomyces pombe Nak1 and Sid1, Saccharomyces cerevisiae sporulation-specific protein 1 (SPS1), and related proteins. Nak1 is required by fission yeast for polarizing the tips of actin cytoskeleton and is involved in cell growth, cell separation, cell morphology and cell-cycle progression. Sid1 is a component in the septation initiation network (SIN) signaling pathway, and plays a role in cytokinesis. SPS1 plays a role in regulating proteins required for spore wall formation. MST4 plays a role in mitogen-activated protein kinase (MAPK) signaling during cytoskeletal rearrangement, morphogenesis, and apoptosis. MST3 phosphorylates the STK NDR and may play a role in cell cycle progression and cell morphology. STK25 may play a role in the regulation of cell migration and polarization. The MST3-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 767984716 172 LGHGNGGTVYKAYHVPSGKILAVKVILLDITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICTEFMDGGS-LD 250
Cdd:cd06609    9 IGKGSFGEVYKGIDKRTNQVVAIKVIDLEEAEDEIEDIQQEIQFLSQCDSPYITKYYGSFLKGSKLWIIMEYCGGGSvLD 88

                         90       100       110
                 ....*....|....*....|....*....|....
gi 767984716 251 V--YRKMPEHVLGRIAVAVVKGLTYLWSLKILHR 282
Cdd:cd06609   89 LlkPGPLDETYIAFILREVLLGLEYLHSEGKIHR 122

Catalytic domain of bacterial Serine/Threonine kinases, PknB and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily includes many bacterial eukaryotic-type STKs including Staphylococcus aureus PknB (also called PrkC or Stk1), Bacillus subtilis PrkC, and Mycobacterium tuberculosis Pkn proteins (PknB, PknD, PknE, PknF, PknL, and PknH), among others. S. aureus PknB is the only eukaryotic-type STK present in this species, although many microorganisms encode for several such proteins. It is important for the survival and pathogenesis of S. aureus as it is involved in the regulation of purine and pyrimidine biosynthesis, cell wall metabolism, autolysis, virulence, and antibiotic resistance. M. tuberculosis PknB is essential for growth and it acts on diverse substrates including proteins involved in peptidoglycan synthesis, cell division, transcription, stress responses, and metabolic regulation. B. subtilis PrkC is located at the inner membrane of endospores and functions to trigger spore germination. Bacterial STKs in this subfamily show varied domain architectures. The well-characterized members such as S. aureus and M. tuberculosis PknB, and B. subtilis PrkC, contain an N-terminal cytosolic kinase domain, a transmembrane (TM) segment, and mutliple C-terminal extracellular PASTA domains. The PknB subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984716 167 RYR--DTLGHGNGGTVYKAYHVPSGKILAVKVILLDITL--ELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICTE 242
Cdd:cd14014    1 RYRlvRLLGRGGMGEVYRARDTLLGRPVAIKVLRPELAEdeEFRERFLREARALARLSHPNIVRVYDVGEDDGRPYIVME 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 767984716 243 FMDGGSLDVY----RKMPEHVLGRIAVAVVKGLTYLWSLKILHR 282
Cdd:cd14014   81 YVEGGSLADLlrerGPLPPREALRILAQIADALAAAHRAGIVHR 124

Catalytic domain of the Serine/Threonine Kinase, p21-activated kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PAKs are Rho family GTPase-regulated kinases that serve as important mediators in the function of Cdc42 (cell division cycle 42) and Rac. PAKs are implicated in the regulation of many cellular processes including growth factor receptor-mediated proliferation, cell polarity, cell motility, cell death and survival, and actin cytoskeleton organization. PAK deregulation is associated with tumor development. PAKs from higher eukaryotes are classified into two groups (I and II), according to their biochemical and structural features. Group I PAKs contain a PBD (p21-binding domain) overlapping with an AID (autoinhibitory domain), a C-terminal catalytic domain, SH3 binding sites and a non-classical SH3 binding site for PIX (PAK-interacting exchange factor). Group II PAKs contain a PBD and a catalytic domain, but lack other motifs found in group I PAKs. Since group II PAKs do not contain an obvious AID, they may be regulated differently from group I PAKs. Group I PAKs interact with the SH3 containing proteins Nck, Grb2 and PIX; no such binding has been demonstrated for group II PAKs. The PAK 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 767984716 172 LGHGNGGTVYKAYHVPSGKILAVKVIllDITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICTEFMDGGSL-D 250
Cdd:cd06614    8 IGEGASGEVYKATDRATGKEVAIKKM--RLRKQNKELIINEILIMKECKHPNIVDYYDSYLVGDELWVVMEYMDGGSLtD 85

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 767984716 251 VYR----KMPEHVLGRIAVAVVKGLTYLWSLKILHR 282
Cdd:cd06614   86 IITqnpvRMNESQIAYVCREVLQGLEYLHSQNVIHR 121

N-terminal Catalytic domain of Class III myosin-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Class III myosins are motor proteins with an N-terminal kinase catalytic domain and a C-terminal actin-binding motor domain. Class III myosins are present in the photoreceptors of invertebrates and vertebrates and in the auditory hair cells of mammals. The kinase domain of myosin III can phosphorylate several cytoskeletal proteins, conventional myosin regulatory light chains, and can autophosphorylate the C-terminal motor domain. Myosin III may play an important role in maintaining the structural integrity of photoreceptor cell microvilli. It may also function as a cargo carrier during light-dependent translocation, in photoreceptor cells, of proteins such as transducin and arrestin. The Drosophila class III myosin, called NinaC (Neither inactivation nor afterpotential protein C), is critical in normal adaptation and termination of photoresponse. Vertebrates contain two isoforms of class III myosin, IIIA and IIIB. This subfamily also includes mammalian NIK-like embryo-specific kinase (NESK), Traf2- and Nck-interacting kinase (TNIK), and mitogen-activated protein kinase (MAPK) kinase kinase kinase 4/6. MAP4Ks are involved in some MAPK signaling pathways by activating a MAPK kinase kinase. MAPK signaling cascades are important in mediating cellular responses to extracellular signals. The class III myosin-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 767984716 170 DTLGHGNGGTVYKAYHVPSGKILAVKVIllDITLELQKQIMSELEILYK-CDSSYIIGFYGAFF------VENRISICTE 242
Cdd:cd06608   12 EVIGEGTYGKVYKARHKKTGQLAAIKIM--DIIEDEEEEIKLEINILRKfSNHPNIATFYGAFIkkdppgGDDQLWLVME 89

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 767984716 243 FMDGGS--------LDVYRKMPEHVLGRIAVAVVKGLTYLWSLKILHR 282
Cdd:cd06608   90 YCGGGSvtdlvkglRKKGKRLKEEWIAYILRETLRGLAYLHENKVIHR 137

Serine/threonine protein kinase [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984716 161 MNEQDI-RYR--DTLGHGNGGTVYKAYHVPSGKILAVKVILLDITL--ELQKQIMSELEILYKCDSSYIIGFYGAFFVEN 235
Cdd:COG0515    1 MSALLLgRYRilRLLGRGGMGVVYLARDLRLGRPVALKVLRPELAAdpEARERFRREARALARLNHPNIVRVYDVGEEDG 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 767984716 236 RISICTEFMDGGSLDVY----RKMPEHVLGRIAVAVVKGLTYLWSLKILHR 282
Cdd:COG0515   81 RPYLVMEYVEGESLADLlrrrGPLPPAEALRILAQLAEALAAAHAAGIVHR 131

Tyrosine kinase, catalytic domain; Phosphotransferases. Tyrosine-specific kinase subfamily.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984716   170 DTLGHGNGGTVYKAYHVPSGKIL----AVKVILLDITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICTEFMD 245
Cdd:smart00219   5 KKLGEGAFGEVYKGKLKGKGGKKkvevAVKTLKEDASEQQIEEFLREARIMRKLDHPNVVKLLGVCTEEEPLYIVMEYME 84

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|..
gi 767984716   246 GGSLDVYRKMPEHVLG-----RIAVAVVKGLTYLWSLKILHR 282
Cdd:smart00219  85 GGDLLSYLRKNRPKLSlsdllSFALQIARGMEYLESKNFIHR 126

Protein kinase; unclassified specificity; Phosphotransferases. The specificity of this class of kinases can not be predicted. Possible dual-specificity Ser/Thr/Tyr kinase.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984716   166 IRYRDTLGHGNGGTVYKA--YHVPSGKIL--AVKVILLDITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICT 241
Cdd:smart00221   1 LTLGKKLGEGAFGEVYKGtlKGKGDGKEVevAVKTLKEDASEQQIEEFLREARIMRKLDHPNIVKLLGVCTEEEPLMIVM 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*..
gi 767984716   242 EFMDGGSLDVY-RKMPEHVLG-----RIAVAVVKGLTYLWSLKILHR 282
Cdd:smart00221  81 EYMPGGDLLDYlRKNRPKELSlsdllSFALQIARGMEYLESKNFIHR 127

Catalytic domain of the Serine/Threonine kinases, Autophagy-related protein 1 and Unc-51-like kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily includes yeast ATG1 and metazoan homologs including vertebrate ULK1-3. The ATG1/ULK complex is conserved from yeast to humans and it plays a critical role in the initiation of autophagy, the intracellular system that leads to the lysosomal degradation of cellular components and their recycling into basic metabolic units. It is involved in nutrient sensing and signaling, the assembly of autophagy factors and the execution of autophagy. In metazoans, ATG1 homologs display additional functions. Unc-51 and ULKs have been implicated in neuronal and axonal development. The ATG1/ULK subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984716 172 LGHGNGGTVYKAYHVPSGKILAVKVILLD-ITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICTEFMDGGSLD 250
Cdd:cd14009    1 IGRGSFATVWKGRHKQTGEVVAIKEISRKkLNKKLQENLESEIAILKSIKHPNIVRLYDVQKTEDFIYLVLEYCAGGDLS 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 767984716 251 VY----RKMPE----HVLGRIAvavvKGLTYLWSLKILHR 282
Cdd:cd14009   81 QYirkrGRLPEavarHFMQQLA----SGLKFLRSKNIIHR 116

Catalytic domain of AMP-activated protein kinase-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The AMPK-like subfamily is composed of AMPK, MARK, BRSK, NUAK, MELK, SNRK, TSSK, and SIK, among others. LKB1 serves as a master upstream kinase that activates AMPK and most AMPK-like kinases. AMPK, also called SNF1 (sucrose non-fermenting1) in yeasts and SnRK1 (SNF1-related kinase1) in plants, is a heterotrimeric enzyme composed of a catalytic alpha subunit and two regulatory subunits, beta and gamma. It is a stress-activated kinase that serves as master regulator of glucose and lipid metabolism by monitoring carbon and energy supplies, via sensing the cell's AMP:ATP ratio. MARKs phosphorylate tau and related microtubule-associated proteins (MAPs), and regulates microtubule-based intracellular transport. They are involved in embryogenesis, epithelial cell polarization, cell signaling, and neuronal differentiation. BRSKs play important roles in establishing neuronal polarity. TSSK proteins are almost exclusively expressed postmeiotically in the testis and play important roles in spermatogenesis and/or spermiogenesis. The AMPK-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 767984716 171 TLGHGNGGTVYKAYHVPSGKILAVKVI-LLDITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICTEFMDGGSL 249
Cdd:cd14003    7 TLGEGSFGKVKLARHKLTGEKVAIKIIdKSKLKEEIEEKIKREIEIMKLLNHPNIIKLYEVIETENKIYLVMEYASGGEL 86

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 767984716 250 DVY----RKMPEHVLGRIAVAVVKGLTYLWSLKILHR 282
Cdd:cd14003   87 FDYivnnGRLSEDEARRFFQQLISAVDYCHSNGIVHR 123

Catalytic domain of Serine/Threonine Kinase 25 (also called Yeast Sps1/Ste20-related kinase 1); STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. STK25 is also called Ste20/oxidant stress response kinase 1 (SOK1) or yeast Sps1/Ste20-related kinase 1 (YSK1). It is localized in the Golgi apparatus through its interaction with the Golgi matrix protein GM130. It may be involved in the regulation of cell migration and polarization. STK25 binds and phosphorylates CCM3 (cerebral cavernous malformation 3), also called PCD10 (programmed cell death 10), and may play a role in apoptosis. Human STK25 is a candidate gene responsible for pseudopseudohypoparathyroidism (PPHP), a disease that shares features with the Albright hereditary osteodystrophy (AHO) phenotype. The STK25 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 767984716 170 DTLGHGNGGTVYKAYHVPSGKILAVKVILLDITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICTEFMDGGS- 248
Cdd:cd06642   10 ERIGKGSFGEVYKGIDNRTKEVVAIKIIDLEEAEDEIEDIQQEITVLSQCDSPYITRYYGSYLKGTKLWIIMEYLGGGSa 89

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 767984716 249 LDVYRKMP--EHVLGRIAVAVVKGLTYLWSLKILHR 282
Cdd:cd06642   90 LDLLKPGPleETYIATILREILKGLDYLHSERKIHR 125

Protein tyrosine and serine/threonine kinase; Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyze the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyze the reverse process. Protein kinases fall into three broad classes, characterized with respect to substrate specificity; Serine/threonine-protein kinases, tyrosine-protein kinases, and dual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins). This entry represents the catalytic domain found in a number of serine/threonine- and tyrosine-protein kinases. It does not include the catalytic domain of dual specificity kinases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984716  166 IRYRDTLGHGNGGTVYKAYHVPSGK----ILAVKVILLDITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISICT 241
Cdd:pfam07714   1 LTLGEKLGEGAFGEVYKGTLKGEGEntkiKVAVKTLKEGADEEEREDFLEEASIMKKLDHPNIVKLLGVCTQGEPLYIVT 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 767984716  242 EFMDGGSLDVY-RKMPEHV----LGRIAVAVVKGLTYLWSLKILHR 282
Cdd:pfam07714  81 EYMPGGDLLDFlRKHKRKLtlkdLLSMALQIAKGMEYLESKNFVHR 126

Catalytic domain of Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 3-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 MEKK3, MEKK2, and related proteins; all contain an N-terminal PB1 domain, which mediates oligomerization, and a C-terminal catalytic domain. MEKK2 and MEKK3 are MAPK kinase kinases (MAPKKKs or MKKK) that activate MEK5 (also called MKK5), which activates ERK5. The ERK5 cascade plays roles in promoting cell proliferation, differentiation, neuronal survival, and neuroprotection. MEKK3 plays an essential role in embryonic angiogenesis and early heart development. MEKK2 and MEKK3 can also activate the MAPKs, c-Jun N-terminal kinase (JNK) and p38, through their respective MAPKKs. The MEKK3-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 767984716 172 LGHGNGGTVYKAYHVPSGKILAVKVILLD-ITLELQKQIMS---ELEILYKCDSSYIIGFYGAFFVENRISICTEFMDGG 247
Cdd:cd06625    8 LGQGAFGQVYLCYDADTGRELAVKQVEIDpINTEASKEVKAlecEIQLLKNLQHERIVQYYGCLQDEKSLSIFMEYMPGG 87