Pseudokinase domain of Scy1-like proteins; The pseudokinase domain shows similarity to protein kinases but lacks crucial residues for catalytic activity. This subfamily is composed of the catalytically inactive kinases with similarity to yeast Scy1. It includes four mammalian proteins called SCY1-like protein 1 (SCYL1), SCYL2, SCYL3, as well as Testis-EXpressed protein 14 (TEX14). SCYL1 binds to and co-localizes with the membrane trafficking coatomer I (COPI) complex, and regulates COPI-mediated vesicle trafficking. Null mutations in the SCYL1 gene are responsible for the pathology in mdf (muscle-deficient) mice which display progressive motor neuropathy. SCYL2, also called coated vesicle-associated kinase of 104 kDa (CVAK104), is involved in the trafficking of clathrin-coated vesicles. It also binds the HIV-1 accessory protein Vpu and acts as a regulatory factor that promotes the dephosphorylation of Vpu, facilitating the restriction of HIV-1 release. SCYL3, also called ezrin-binding protein PACE-1, may be involved in regulating cell adhesion and migration. TEX14 is required for spermatogenesis and male fertility. It localizes to kinetochores (KT) during mitosis and is a target of the mitotic kinase PLK1. It regulates the maturation of the outer KT and the KT-microtubule attachment. The SCY1-like 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 119618038   1 MVHGNITPENIILNKSGAWKIMGFDFCVSSTNPSEQEPKFpcKEWDPNLPSLCLPNPEYLAPEYILSVSCETASDMYSLG 80
Cdd:cd14011  136 LVHGNICPESVVINSNGEWKLAGFDFCISSEQATDQFPYF--REYDPNLPPLAQPNLNYLAPEYILSKTCDPASDMFSLG 213

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 119618038  81 TVMYAVFNKGKPIFE-VNKQDIYKSFSRQLDQLSRlgsSSLTNIPEEVREHVKLLLNVTPTVRPDADQMTKIPFFDD 156
Cdd:cd14011  214 VLIYAIYNKGKPLFDcVNNLLSYKKNSNQLRQLSL---SLLEKVPEELRDHVKTLLNVTPEVRPDAEQLSKIPFFDD 287

Pseudokinase domain of Scy1-like proteins; The pseudokinase domain shows similarity to protein kinases but lacks crucial residues for catalytic activity. This subfamily is composed of the catalytically inactive kinases with similarity to yeast Scy1. It includes four mammalian proteins called SCY1-like protein 1 (SCYL1), SCYL2, SCYL3, as well as Testis-EXpressed protein 14 (TEX14). SCYL1 binds to and co-localizes with the membrane trafficking coatomer I (COPI) complex, and regulates COPI-mediated vesicle trafficking. Null mutations in the SCYL1 gene are responsible for the pathology in mdf (muscle-deficient) mice which display progressive motor neuropathy. SCYL2, also called coated vesicle-associated kinase of 104 kDa (CVAK104), is involved in the trafficking of clathrin-coated vesicles. It also binds the HIV-1 accessory protein Vpu and acts as a regulatory factor that promotes the dephosphorylation of Vpu, facilitating the restriction of HIV-1 release. SCYL3, also called ezrin-binding protein PACE-1, may be involved in regulating cell adhesion and migration. TEX14 is required for spermatogenesis and male fertility. It localizes to kinetochores (KT) during mitosis and is a target of the mitotic kinase PLK1. It regulates the maturation of the outer KT and the KT-microtubule attachment. The SCY1-like 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 119618038   1 MVHGNITPENIILNKSGAWKIMGFDFCVSSTNPSEQEPKFpcKEWDPNLPSLCLPNPEYLAPEYILSVSCETASDMYSLG 80
Cdd:cd14011  136 LVHGNICPESVVINSNGEWKLAGFDFCISSEQATDQFPYF--REYDPNLPPLAQPNLNYLAPEYILSKTCDPASDMFSLG 213

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 119618038  81 TVMYAVFNKGKPIFE-VNKQDIYKSFSRQLDQLSRlgsSSLTNIPEEVREHVKLLLNVTPTVRPDADQMTKIPFFDD 156
Cdd:cd14011  214 VLIYAIYNKGKPLFDcVNNLLSYKKNSNQLRQLSL---SLLEKVPEELRDHVKTLLNVTPEVRPDAEQLSKIPFFDD 287

Protein kinase domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119618038   57 PEYLAPEYILSVSCETASDMYSLGTVMYAVFNkGKPIFE-VNKQDIYKSFSRQLDQLSRLGSssltNIPEEVREHVKLLL 135
Cdd:pfam00069 124 PWYMAPEVLGGNPYGPKVDVWSLGCILYELLT-GKPPFPgINGNEIYELIIDQPYAFPELPS----NLSEEAKDLLKKLL 198

                          90
                  ....*....|....*....
gi 119618038  136 NVTPTVRPDADQMTKIPFF 154
Cdd:pfam00069 199 KKDPSKRLTATQALQHPWF 217

serine/threonine protein kinase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119618038   1 MVHGNITPENIILNKSGAWKIMGFDFC-VSSTNPSEQEPKFPCKewdpnlpslclpNPEYLAPEYILSVSCETASDMYSL 79
Cdd:PTZ00283 164 MIHRDIKSANILLCSNGLVKLGDFGFSkMYAATVSDDVGRTFCG------------TPYYVAPEIWRRKPYSKKADMFSL 231

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 119618038  80 GTVMYAVFNKGKPIFEVNKQDI-YKSFSRQLDQLSrlgssslTNIPEEVREHVKLLLNVTPTVRPDADQMTKIP 152
Cdd:PTZ00283 232 GVLLYELLTLKRPFDGENMEEVmHKTLAGRYDPLP-------PSISPEMQEIVTALLSSDPKRRPSSSKLLNMP 298

Pseudokinase domain of Scy1-like proteins; The pseudokinase domain shows similarity to protein kinases but lacks crucial residues for catalytic activity. This subfamily is composed of the catalytically inactive kinases with similarity to yeast Scy1. It includes four mammalian proteins called SCY1-like protein 1 (SCYL1), SCYL2, SCYL3, as well as Testis-EXpressed protein 14 (TEX14). SCYL1 binds to and co-localizes with the membrane trafficking coatomer I (COPI) complex, and regulates COPI-mediated vesicle trafficking. Null mutations in the SCYL1 gene are responsible for the pathology in mdf (muscle-deficient) mice which display progressive motor neuropathy. SCYL2, also called coated vesicle-associated kinase of 104 kDa (CVAK104), is involved in the trafficking of clathrin-coated vesicles. It also binds the HIV-1 accessory protein Vpu and acts as a regulatory factor that promotes the dephosphorylation of Vpu, facilitating the restriction of HIV-1 release. SCYL3, also called ezrin-binding protein PACE-1, may be involved in regulating cell adhesion and migration. TEX14 is required for spermatogenesis and male fertility. It localizes to kinetochores (KT) during mitosis and is a target of the mitotic kinase PLK1. It regulates the maturation of the outer KT and the KT-microtubule attachment. The SCY1-like 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 119618038   1 MVHGNITPENIILNKSGAWKIMGFDFCVSSTNPSEQEPKFpcKEWDPNLPSLCLPNPEYLAPEYILSVSCETASDMYSLG 80
Cdd:cd14011  136 LVHGNICPESVVINSNGEWKLAGFDFCISSEQATDQFPYF--REYDPNLPPLAQPNLNYLAPEYILSKTCDPASDMFSLG 213

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 119618038  81 TVMYAVFNKGKPIFE-VNKQDIYKSFSRQLDQLSRlgsSSLTNIPEEVREHVKLLLNVTPTVRPDADQMTKIPFFDD 156
Cdd:cd14011  214 VLIYAIYNKGKPLFDcVNNLLSYKKNSNQLRQLSL---SLLEKVPEELRDHVKTLLNVTPEVRPDAEQLSKIPFFDD 287

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 119618038   1 MVHGNITPENIILNKSGAWKIMGFDFCVSSTNPSEQEPKFPckewdpnlpslCLPNPEYLAPEYILSVSCETASDMYSLG 80
Cdd:cd00180  113 IIHRDLKPENILLDSDGTVKLADFGLAKDLDSDDSLLKTTG-----------GTTPPYYAPPELLGGRYYGPKVDIWSLG 181

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 119618038  81 TVMYAVfnkgkpifevnkqdiyksfsrqldqlsrlgsssltnipEEVREHVKLLLNVTPTVRPDADQMTKIP 152
Cdd:cd00180  182 VILYEL--------------------------------------EELKDLIRRMLQYDPKKRPSAKELLEHL 215

Protein kinase domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119618038   57 PEYLAPEYILSVSCETASDMYSLGTVMYAVFNkGKPIFE-VNKQDIYKSFSRQLDQLSRLGSssltNIPEEVREHVKLLL 135
Cdd:pfam00069 124 PWYMAPEVLGGNPYGPKVDVWSLGCILYELLT-GKPPFPgINGNEIYELIIDQPYAFPELPS----NLSEEAKDLLKKLL 198

                          90
                  ....*....|....*....
gi 119618038  136 NVTPTVRPDADQMTKIPFF 154
Cdd:pfam00069 199 KKDPSKRLTATQALQHPWF 217

Catalytic domain of the Serine/Threonine kinase, Mitogen-activated protein kinase-activated protein kinase 3; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MAPK-activated protein kinase 3 (MAPKAP3 or MK3) contains an N-terminal proline-rich region that can bind to SH3 domains, a catalytic kinase domain followed by a C-terminal autoinhibitory region that contains nuclear localization (NLS) and nuclear export (NES) signals with a p38 MAPK docking motif that overlaps the NLS. MK3 is a bonafide substrate for the MAPK p38. It is closely related to MK2 and thus far, MK2/3 show indistinguishable substrate specificity. They are mainly involved in the regulation of gene expression and they participate in diverse cellular processes such as endocytosis, cytokine production, cytoskeletal reorganization, cell migration, cell cycle control and chromatin remodeling. They are implicated in inflammation and cance and their substrates include mRNA-AU-rich-element (ARE)-binding proteins (TTP and hnRNP A0), Hsp proteins (Hsp27 and Hsp25) and RSK, among others. MK2/3 are both expressed ubiquitously but MK2 is expressed at significantly higher levels. MK3 activity is only significant when MK2 is absent. The MK3 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 119618038   1 MVHGNITPENIIL---NKSGAWKIMGFDFCVSST--NPSEQepkfPCKewdpnlpslclpNPEYLAPEYILSVSCETASD 75
Cdd:cd14172  124 IAHRDVKPENLLYtskEKDAVLKLTDFGFAKETTvqNALQT----PCY------------TPYYVAPEVLGPEKYDKSCD 187

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119618038  76 MYSLGTVMYAVFNKGKPIFEVNKQDIYKSFSRQLdqlsRLGSSSLTN-----IPEEVREHVKLLLNVTPTVRPDADQMTK 150
Cdd:cd14172  188 MWSLGVIMYILLCGFPPFYSNTGQAISPGMKRRI----RMGQYGFPNpewaeVSEEAKQLIRHLLKTDPTERMTITQFMN 263

                 ...
gi 119618038 151 IPF 153
Cdd:cd14172  264 HPW 266

Serine/threonine protein kinase [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119618038   1 MVHGNITPENIILNKSGAWKIMgfDF-CVSSTNPSEQEPkfpckewdpnlPSLCLPNPEYLAPEYILSVSCETASDMYSL 79
Cdd:COG0515  128 IVHRDIKPANILLTPDGRVKLI--DFgIARALGGATLTQ-----------TGTVVGTPGYMAPEQARGEPVDPRSDVYSL 194

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119618038  80 GTVMYAVFNkGKPIFEVnkQDIYKSFSRQLDQLSRLGSSSLTNIPEEVREHVKLLLNVTPTVRP-DADQM 148
Cdd:COG0515  195 GVTLYELLT-GRPPFDG--DSPAELLRAHLREPPPPPSELRPDLPPALDAIVLRALAKDPEERYqSAAEL 261

Catalytic subunit of the Serine/Threonine Kinases, cAMP-dependent protein 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 cAMP-dependent protein kinases, PKA and PRKX, and similar proteins. The inactive PKA holoenzyme is a heterotetramer composed of two phosphorylated and active catalytic subunits with a dimer of regulatory (R) subunits. Activation is achieved through the binding of the important second messenger cAMP to the R subunits, which leads to the dissociation of PKA into the R dimer and two active subunits. PKA is present ubiquitously in cells and interacts with many different downstream targets. It plays a role in the regulation of diverse processes such as growth, development, memory, metabolism, gene expression, immunity, and lipolysis. PRKX is also reulated by the R subunit and is is present in many tissues including fetal and adult brain, kidney, and lung. It is implicated in granulocyte/macrophage lineage differentiation, renal cell epithelial migration, and tubular morphogenesis in the developing kidney. The PKA-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 119618038   8 PENIILNKSGAWKIMGFDFCvsstnpseqepkfpcKEWDPNLPSLClPNPEYLAPEYILSVSCETASDMYSLGTVMYAVF 87
Cdd:cd05580  129 PENLLLDSDGHIKITDFGFA---------------KRVKDRTYTLC-GTPEYLAPEIILSKGHGKAVDWWALGILIYEML 192

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119618038  88 NKGKPIFEVNKQDIYK-------SFSRQLDqlsrlgsssltnipEEVREHVKLLLNVTPTVR-----PDADQMTKIPFFD 155
Cdd:cd05580  193 AGYPPFFDENPMKIYEkilegkiRFPSFFD--------------PDAKDLIKRLLVVDLTKRlgnlkNGVEDIKNHPWFA 258

                        170
                 ....*....|....*..
gi 119618038 156 DVGavtlqyFDTLFQRD 172
Cdd:cd05580  259 GID------WDALLQRK 269

Catalytic domain of the Serine/Threonine kinase, Aurora-A kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Aurora kinases are key regulators of mitosis and are essential for the accurate and equal division of genomic material from parent to daughter cells. Vertebrates contain at least 2 Aurora kinases (A and B); mammals contains a third Aurora kinase gene (C). Aurora-A regulates cell cycle events from the late S-phase through the M-phase including centrosome maturation, mitotic entry, centrosome separation, spindle assembly, chromosome alignment, cytokinesis, and mitotic exit. Aurora-A activation depends on its autophosphorylation and binding to the microtubule-associated protein TPX2, which also localizes the kinase to spindle microtubules. Aurora-A is overexpressed in many cancer types such as prostate, ovarian, breast, bladder, gastric, and pancreatic. The Aurora 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 119618038   1 MVHGNITPENIILNKSGAWKIMGFDFCVSStnPSEQEPKFpCKEWDpnlpslclpnpeYLAPEYILSVSCETASDMYSLG 80
Cdd:cd14116  126 VIHRDIKPENLLLGSAGELKIADFGWSVHA--PSSRRTTL-CGTLD------------YLPPEMIEGRMHDEKVDLWSLG 190

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 119618038  81 TVMYAvFNKGKPIFEVNK-QDIYKsfsrqldQLSRLGSSSLTNIPEEVREHVKLLLNVTPTVRP 143
Cdd:cd14116  191 VLCYE-FLVGKPPFEANTyQETYK-------RISRVEFTFPDFVTEGARDLISRLLKHNPSQRP 246

Catalytic domain of Dual-specificity tYrosine-phosphorylated and -Regulated Kinase-like protein kinases; Dual-specificity PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine (S/T) as well as tyrosine residues on protein substrates. This subfamily is composed of the dual-specificity DYRKs and YAK1, as well as the S/T kinases (STKs), HIPKs. DYRKs and YAK1 autophosphorylate themselves on tyrosine residues and phosphorylate their substrates exclusively on S/T residues. Proteins in this subfamily play important roles in cell proliferation, differentiation, survival, growth, and development. The DYRK-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 119618038   1 MVHGNITPENIILNKSGAWKIMGFDFCVSSTNPSEQepkfpckewdpnlpSLCLPNPEYLAPEYILSVSCETASDMYSLG 80
Cdd:cd14133  123 LIHCDLKPENILLASYSRCQIKIIDFGSSCFLTQRL--------------YSYIQSRYYRAPEVILGLPYDEKIDMWSLG 188

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 119618038  81 TVMYAVFNkGKPIFEVNkqDIYKSFSRQLDQLSRLGSSSLTNIPEEVREHVKLL---LNVTPTVRPDADQMTKIPFF 154
Cdd:cd14133  189 CILAELYT-GEPLFPGA--SEVDQLARIIGTIGIPPAHMLDQGKADDELFVDFLkklLEIDPKERPTASQALSHPWL 262

Catalytic domain of fungal Rim15-like Protein Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Members of this group include Saccharomyces cerevisiae Rim15, Schizosaccharomyces pombe cek1, and similar fungal proteins. They contain a central catalytic domain, which contains an insert relative to MAST kinases. In addition, Rim15 contains a C-terminal signal receiver (REC) domain while cek1 contains an N-terminal PAS domain. Rim15 (or Rim15p) functions as a regulator of meiosis. It acts as a downstream effector of PKA and regulates entry into stationary phase (G0). Thus, it plays a crucial role in regulating yeast proliferation, differentiation, and aging. Cek1 may facilitate progression of mitotic anaphase. The Rim15-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 119618038   1 MVHGNITPENIILNKSGAWKIMgfDFCVSSTN-PSEQEPKFpckewdpnlpslcLPNPEYLAPEYILSVSCETASDMYSL 79
Cdd:cd05611  118 IIHRDIKPENLLIDQTGHLKLT--DFGLSRNGlEKRHNKKF-------------VGTPDYLAPETILGVGDDKMSDWWSL 182

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119618038  80 GTVMYAvFNKGKPIFEVNKQDiyKSFSRQLDQLSRLGSSSLTNIPEEVREHVKLLLNVTPTVRPDADQMTKI---PFFDD 156
Cdd:cd05611  183 GCVIFE-FLFGYPPFHAETPD--AVFDNILSRRINWPEEVKEFCSPEAVDLINRLLCMDPAKRLGANGYQEIkshPFFKS 259

                 .
gi 119618038 157 V 157
Cdd:cd05611  260 I 260

Catalytic domain of Microtubule-associated serine/threonine (MAST) kinase-like proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily includes MAST kinases, MAST-like (MASTL) kinases (also called greatwall kinase or Gwl), and fungal kinases with similarity to Saccharomyces cerevisiae Rim15 and Schizosaccharomyces pombe cek1. MAST kinases contain an N-terminal domain of unknown function, a central catalytic domain, and a C-terminal PDZ domain that mediates protein-protein interactions. MASTL kinases carry only a catalytic domain which contains a long insert relative to other kinases. The fungal kinases in this subfamily harbor other domains in addition to a central catalytic domain, which like in MASTL, also contains an insert relative to MAST kinases. Rim15 contains a C-terminal signal receiver (REC) domain while cek1 contains an N-terminal PAS domain. MAST kinases are cytoskeletal associated kinases of unknown function that are also expressed at neuromuscular junctions and postsynaptic densities. MASTL/Gwl is involved in the regulation of mitotic entry, mRNA stabilization, and DNA checkpoint recovery. The fungal proteins Rim15 and cek1 are involved in the regulation of meiosis and mitosis, respectively. The MAST-like kinase 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 119618038   2 VHGNITPENIILNKSGAWKIMgfDFCVSSTNPSEQEPKFPCKEWDPNLPSL----CLPNPEYLAPEYILSVSCETASDMY 77
Cdd:cd05579  115 IHRDLKPDNILIDANGHLKLT--DFGLSKVGLVRRQIKLSIQKKSNGAPEKedrrIVGTPDYLAPEILLGQGHGKTVDWW 192

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119618038  78 SLGTVMYAvFNKGKPIFEVNKQDiyKSFSRQLDqlSRLGSSSLTNIPEEVREHVKLLLNVTPTVRPDADQMTKI---PFF 154
Cdd:cd05579  193 SLGVILYE-FLVGIPPFHAETPE--EIFQNILN--GKIEWPEDPEVSDEAKDLISKLLTPDPEKRLGAKGIEEIknhPFF 267

                 ...
gi 119618038 155 DDV 157
Cdd:cd05579  268 KGI 270

Catalytic domain of the Serine/Threonine Kinase, Phosphorylase kinase Gamma 2 subunit; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Phosphorylase kinase (PhK) catalyzes the phosphorylation of inactive phosphorylase b to form the active phosphorylase a. It coordinates hormonal, metabolic, and neuronal signals to initiate the breakdown of glycogen stores, which enables the maintenance of blood-glucose homeostasis during fasting, and is also used as a source of energy for muscle contraction. PhK is one of the largest and most complex protein kinases, composed of a heterotetramer containing four molecules each of four subunit types: one catalytic (gamma) and three regulatory (alpha, beta, and delta). The gamma 2 subunit (PhKG2) is also referred to as the testis/liver gamma isoform. Mutations in its gene cause autosomal-recessive glycogenosis of the liver. The gamma subunit, when isolated, is constitutively active and does not require phosphorylation of the A-loop for activity. The regulatory subunits restrain this kinase activity until signals are received to relieve this inhibition. For example, the kinase is activated in response to hormonal stimulation, after autophosphorylation or phosphorylation by cAMP-dependent kinase of the alpha and beta subunits. The high-affinity binding of ADP to the beta subunit also stimulates kinase activity, whereas calcium relieves inhibition by binding to the delta (calmodulin) subunit. The PhKG2 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 119618038   1 MVHGNITPENIILNKSGAWKIMGFDFCVsSTNPSEQepkfpckewdpnLPSLClPNPEYLAPEyILSVSCETAS------ 74
Cdd:cd14181  137 IVHRDLKPENILLDDQLHIKLSDFGFSC-HLEPGEK------------LRELC-GTPGYLAPE-ILKCSMDETHpgygke 201

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119618038  75 -DMYSLGTVMYAVFnKGKPIFEVNKQDIYksFSRQLDQLSRLGSSSLTNIPEEVREHVKLLLNVTPTVRPDADQMTKIPF 153
Cdd:cd14181  202 vDLWACGVILFTLL-AGSPPFWHRRQMLM--LRMIMEGRYQFSSPEWDDRSSTVKDLISRLLVVDPEIRLTAEQALQHPF 278

                 .
gi 119618038 154 F 154
Cdd:cd14181  279 F 279

Catalytic domain of the Serine/Threonine kinase, Inositol-requiring protein 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. IRE1, also called Endoplasmic reticulum (ER)-to-nucleus signaling protein (or ERN), is an ER-localized type I transmembrane protein with kinase and endoribonuclease domains in the cytoplasmic side. It acts as an ER stress sensor and is the oldest and most conserved component of the unfolded protein response (UPR) in eukaryotes. The UPR is activated when protein misfolding is detected in the ER in order to decrease the synthesis of new proteins and increase the capacity of the ER to cope with the stress. During ER stress, IRE1 dimerizes and forms oligomers, allowing the kinase domain to undergo trans-autophosphorylation. This leads to a conformational change that stimulates its endoribonuclease activity and results in the cleavage of its mRNA substrate, HAC1 in yeast and XBP1 in metazoans, promoting a splicing event that enables translation into a transcription factor which activates the UPR. Mammals contain two IRE1 proteins, IRE1alpha (or ERN1) and IRE1beta (or ERN2). The Ire1 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 119618038   2 VHGNITPENIIL---NKSGAWKIMGFDFCVsstnpseqepkfpCKEWDPNLPSL-CLPNPE----YLAPEyILSVSCET- 72
Cdd:cd13982  121 VHRDLKPQNILIstpNAHGNVRAMISDFGL-------------CKKLDVGRSSFsRRSGVAgtsgWIAPE-MLSGSTKRr 186

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119618038  73 ---ASDMYSLGTVMYAVFNKGKPIFEvnkqdiyKSFSRQ---------LDQLSRLGSSsltniPEEVREHVKLLLNVTPT 140
Cdd:cd13982  187 qtrAVDIFSLGCVFYYVLSGGSHPFG-------DKLEREanilkgkysLDKLLSLGEH-----GPEAQDLIERMIDFDPE 254

                        170
                 ....*....|....
gi 119618038 141 VRPDADQMTKIPFF 154
Cdd:cd13982  255 KRPSAEEVLNHPFF 268

Catalytic domain of the Serine/Threonine Kinase, Polo-like kinase 3; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PLKs play important roles in cell cycle progression and in DNA damage responses. They regulate mitotic entry, mitotic exit, and cytokinesis. In general PLKs contain an N-terminal catalytic kinase domain and a C-terminal regulatory polo box domain (PBD), which is comprised by two bipartite polo-box motifs (or polo boxes) and is involved in protein interactions. There are five mammalian PLKs (PLK1-5) from distinct genes. PLK3, also called Prk or Fnk (FGF-inducible kinase), regulates angiogenesis and responses to DNA damage. Activated PLK3 mediates Chk2 phosphorylation by ATM and the resulting checkpoint activation. PLK3 phosphorylates DNA polymerase delta and may be involved in DNA repair. It also inhibits Cdc25c, thereby regulating the onset of mitosis. The PLK3 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 119618038   1 MVHGNITPENIILNKSGAWKIMGFDFcVSSTNPSEQEPKFPCKewdpnlpslclpNPEYLAPEYILSVSCETASDMYSLG 80
Cdd:cd14189  122 ILHRDLKLGNFFINENMELKVGDFGL-AARLEPPEQRKKTICG------------TPNYLAPEVLLRQGHGPESDVWSLG 188

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 119618038  81 TVMYAVFNkGKPIFEVnkQDIYKSFsRQLDQLSRLGSSSLTnipEEVREHVKLLLNVTPTVRPDADQMTKIPFF 154
Cdd:cd14189  189 CVMYTLLC-GNPPFET--LDLKETY-RCIKQVKYTLPASLS---LPARHLLAGILKRNPGDRLTLDQILEHEFF 255

Catalytic kinase domain of Myosin Light Chain Kinase-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This family is composed of MLCKs and related MLCK-like kinase domains from giant STKs such as titin, obscurin, SPEG, Unc-89, Trio, kalirin, and Twitchin. Also included in this family are Death-Associated Protein Kinases (DAPKs) and Death-associated protein kinase-Related Apoptosis-inducing protein Kinase (DRAKs). MLCK phosphorylates myosin regulatory light chain and controls the contraction of all muscle types. Titin, obscurin, Twitchin, and SPEG are muscle proteins involved in the contractile apparatus. The giant STKs are multidomain proteins containing immunoglobulin (Ig), fibronectin type III (FN3), SH3, RhoGEF, PH and kinase domains. Titin, obscurin, Twitchin, and SPEG contain many Ig domain repeats at the N-terminus, while Trio and Kalirin contain spectrin-like repeats. The MLCK-like family 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 119618038   2 VHGNITPENIILNKSGAWKIMGFDFCVSstnpseqepkfpcKEWDPNLPSLCL-PNPEYLAPEYILSVSCETASDMYSLG 80
Cdd:cd14006  111 LHLDLKPENILLADRPSPQIKIIDFGLA-------------RKLNPGEELKEIfGTPEFVAPEIVNGEPVSLATDMWSIG 177

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 119618038  81 TVMYAVFNKGKPIFEVNKQDIYKSFSRQLDQLSRLGSSSLTnipEEVREHVKLLLNVTPTVRPDADQ 147
Cdd:cd14006  178 VLTYVLLSGLSPFLGEDDQETLANISACRVDFSEEYFSSVS---QEAKDFIRKLLVKEPRKRPTAQE 241

The catalytic domain of the Serine/Threonine Kinase, Death-associated protein kinase-Related Apoptosis-inducing protein Kinase 2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. DRAKs were named based on their similarity (around 50% identity) to the kinase domain of DAPKs. They contain an N-terminal kinase domain and a C-terminal regulatory domain. Vertebrates contain two subfamily members, DRAK1 and DRAK2 (also called STK17B). Both DRAKs are localized to the nucleus, autophosphorylate themselves, and phosphorylate myosin light chain as a substrate. DRAK2 has been implicated in inducing or enhancing apoptosis in beta cells, fibroblasts, and lymphoid cells, where it is highly expressed. It is involved in regulating many immune processes including the germinal center (GC) reaction, responses to thymus-dependent antigens, activated T cell survival, memory T cell responses. It may be involved in the development of autoimmunity. The DRAK2 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 119618038   1 MVHGNITPENIIL---NKSGAWKIMGFDFCVSSTNPSEQEPkfpckewdpnlpslCLPNPEYLAPEYILSVSCETASDMY 77
Cdd:cd14198  131 IVHLDLKPQNILLssiYPLGDIKIVDFGMSRKIGHACELRE--------------IMGTPEYLAPEILNYDPITTATDMW 196

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 119618038  78 SLGTVMYAVFNKGKPIFEVNKQDIYKSFSRQLDQLSRlgsSSLTNIPEEVREHVKLLLNVTPTVRPDAD 146
Cdd:cd14198  197 NIGVIAYMLLTHESPFVGEDNQETFLNISQVNVDYSE---ETFSSVSQLATDFIQKLLVKNPEKRPTAE 262

Catalytic subunit of the Serine/Threonine Kinase, cAMP-dependent protein kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The inactive PKA holoenzyme is a heterotetramer composed of two phosphorylated and active catalytic subunits with a dimer of regulatory (R) subunits. Activation is achieved through the binding of the important second messenger cAMP to the R subunits, which leads to the dissociation of PKA into the R dimer and two active subunits. PKA is present ubiquitously in cells and interacts with many different downstream targets. It plays a role in the regulation of diverse processes such as growth, development, memory, metabolism, gene expression, immunity, and lipolysis. The PKA 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 119618038   1 MVHGNITPENIILNKSGAWKIMGFDFCvsstnpseqepkfpcKEWDPNLPSLClPNPEYLAPEYILSVSCETASDMYSLG 80
Cdd:cd14209  122 LIYRDLKPENLLIDQQGYIKVTDFGFA---------------KRVKGRTWTLC-GTPEYLAPEIILSKGYNKAVDWWALG 185

                         90
                 ....*....|....
gi 119618038  81 TVMYAvFNKGKPIF 94
Cdd:cd14209  186 VLIYE-MAAGYPPF 198

Catalytic domain of the Serine/Threonine kinase, eukaryotic translation Initiation Factor 2-Alpha Kinase 2 or Heme-Regulated Inhibitor kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. HRI (or EIF2AK1) contains an N-terminal regulatory heme-binding domain and a C-terminal catalytic kinase domain. It is suppressed under normal conditions by binding of the heme iron, and is activated during heme deficiency. It functions as a critical regulator that ensures balanced synthesis of globins and heme, in order to form stable hemoglobin during erythroid differentiation and maturation. HRI also protects cells and enhances survival under iron-deficient conditions. EIF2AKs phosphorylate the alpha subunit of eIF-2, resulting in the downregulation of protein synthesis. The HRI 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 119618038   1 MVHGNITPENIILNKSGAWKIMGfDFCVSSTNPSEQEPKFPCKEWDPNLPSLC-LPNPEYLAPEYILSVSCETASDMYSL 79
Cdd:cd14049  141 IVHRDLKPRNIFLHGSDIHVRIG-DFGLACPDILQDGNDSTTMSRLNGLTHTSgVGTCLYAAPEQLEGSHYDFKSDMYSI 219

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 119618038  80 GTVMYAVF-------NKGKPIFEVNKQDIYKSFSRQLdqlsrlgsssltniPEEVrEHVKLLLNVTPTVRPDADQMT 149
Cdd:cd14049  220 GVILLELFqpfgtemERAEVLTQLRNGQIPKSLCKRW--------------PVQA-KYIKLLTSTEPSERPSASQLL 281

Catalytic domain of the Serine/Threonine kinase, Unc-51-like kinase 4; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. ULK4 is a functionally uncharacterized kinase that shows similarity to ATG1/ULKs. 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. The ULK4 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 119618038   1 MVHGNITPENIILNKSGAWKImgFDFCVS------STNPSEQEPKfPCKEWDPNLPSLCLPNPEYLAPEYILSVSCETAS 74
Cdd:cd14010  115 IIYCDLKPSNILLDGNGTLKL--SDFGLArregeiLKELFGQFSD-EGNVNKVSKKQAKRGTPYYMAPELFQGGVHSFAS 191

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119618038  75 DMYSLGTVMYAVFNkGKPIFEVNkqdiykSFSRQLDQ-LSR----LGSSSLTNIPEEVREHVKLLLNVTPTVRPDADQMT 149
Cdd:cd14010  192 DLWALGCVLYEMFT-GKPPFVAE------SFTELVEKiLNEdpppPPPKVSSKPSPDFKSLLKGLLEKDPAKRLSWDELV 264

                 ....
gi 119618038 150 KIPF 153
Cdd:cd14010  265 KHPF 268

Catalytic domain of the Serine/Threonine Kinase, Protein Kinase B beta (also called Akt2); STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PKB-beta is the predominant PKB isoform expressed in insulin-responsive tissues. It plays a critical role in the regulation of glucose homeostasis. It is also implicated in muscle cell differentiation. Mice deficient in PKB-beta display normal growth weights but exhibit severe insulin resistance and diabetes, accompanied by lipoatrophy and B-cell failure. PKB contains an N-terminal pleckstrin homology (PH) domain and a C-terminal catalytic domain.The PKB-beta 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 119618038   1 MVHGNITPENIILNKSGAWKIMGFDFCVSSTNPseqepkfpckewDPNLPSLClPNPEYLAPEYILSVSCETASDMYSLG 80
Cdd:cd05595  116 VVYRDIKLENLMLDKDGHIKITDFGLCKEGITD------------GATMKTFC-GTPEYLAPEVLEDNDYGRAVDWWGLG 182

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119618038  81 TVMYAVFNKGKPIFEVNKQDIYK-------SFSRQL--------------DQLSRLGSSSltNIPEEVREHvKLLLNV-- 137
Cdd:cd05595  183 VVMYEMMCGRLPFYNQDHERLFElilmeeiRFPRTLspeaksllagllkkDPKQRLGGGP--SDAKEVMEH-RFFLSInw 259

                        170       180
                 ....*....|....*....|....*..
gi 119618038 138 --------TPTVRPDADQMTKIPFFDD 156
Cdd:cd05595  260 qdvvqkklLPPFKPQVTSEVDTRYFDD 286

C-terminal catalytic domain of the Serine/Threonine Kinase, Mitogen and stress-activated kinase 2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MSK2 and MSK1 play nonredundant roles in activating histone H3 kinases, which play pivotal roles in compaction of the chromatin fiber. MSK2 is the required H3 kinase in response to stress stimuli and activation of the p38 MAPK pathway. MSK2 also plays a role in the pathogenesis of psoriasis. MSKs contain an N-terminal kinase domain (NTD) from the AGC family and a C-terminal kinase domain (CTD) from the CAMK family, similar to 90 kDa ribosomal protein S6 kinases (RSKs). MSKs are activated by two major signaling cascades, the Ras-MAPK and p38 stress kinase pathways, which trigger phosphorylation in the activation loop (A-loop) of the CTD of MSK. The active CTD phosphorylates the hydrophobic motif (HM) of NTD, which facilitates the phosphorylation of the A-loop and activates the NTD, which in turn phosphorylates downstream targets. The MSK2 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 119618038   1 MVHGNITPENIILNKSG---AWKIMGFDFCVSSTNPSE--QEPKFPCkewdpnlpslclpnpEYLAPEYILSVSCETASD 75
Cdd:cd14180  122 VVHRDLKPENILYADESdgaVLKVIDFGFARLRPQGSRplQTPCFTL---------------QYAAPELFSNQGYDESCD 186

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 119618038  76 MYSLGTVMYAVFNkGKPIFEVNKQDIYKSFSRQLDQLSRLGSSSL-----TNIPEEVREHVKLLLNVTPTVR 142
Cdd:cd14180  187 LWSLGVILYTMLS-GQVPFQSKRGKMFHNHAADIMHKIKEGDFSLegeawKGVSEEAKDLVRGLLTVDPAKR 257