zinc-ribbon domain; This family consists of a single zinc ribbon domain, ie half of a pair as in family DZR. pfam12773.

                          10        20
                  ....*....|....*....|.
gi 2469480083   4 FCPVCGKSVKVSFKFCPYCGK 24
Cdd:pfam13240   1 FCPNCGAENPDGAKFCPKCGA 21

putative serine/threonine kinase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 134 GTELTDQNGKHWTLGALQIRDDQGILYEaepTSAVPSESRTQKwrFSLKLDS-KDGRLFNEQNFFQRVAKPLQVNKWKKQ 212
Cdd:PHA02882    3 GIPLIDITGKEWKIDKLIGCGGFGCVYE---TQCASDHCINNQ--AVAKIENlENETIVMETLVYNNIYDIDKIALWKNI 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 213 FLLPLLAIPT---CIGFGIHQDKYRFLVFPSL---GRSLQSALDDNPKHVVSercvlQVACRLLDALEYLHENEYVHGNL 286
Cdd:PHA02882   78 HNIDHLGIPKyygCGSFKRCRMYYRFILLEKLvenTKEIFKRIKCKNKKLIK-----NIMKDMLTTLEYIHEHGISHGDI 152

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 287 TAENVFVNPEDLSQvtLVGYGFTYRYCPGGKHVAYKEGSRSPHDGDLEFISMDLHKGCGPSRRSDLQTLGYCMLKWLYGS 366
Cdd:PHA02882  153 KPENIMVDGNNRGY--IIDYGIASHFIIHGKHIEYSKEQKDLHRGTLYYAGLDAHNGACVTRRGDLESLGYCMLKWAGIK 230

                  ...
gi 2469480083 367 LPW 369
Cdd:PHA02882  231 LPW 233

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

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2469480083  226 FGIHQDK-YRFLVFPSL-GRSLQSALDDNPKhvVSERCVLQVACRLLDALEYLHENEYVHGNLTAENVFVN 294
Cdd:smart00220  63 YDVFEDEdKLYLVMEYCeGGDLFDLLKKRGR--LSEDEARFYLRQILSALEYLHSKGIVHRDLKPENILLD 131

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
                  ....*....|....*....|....*....|..
gi 2469480083 263 LQVACrlldALEYLHENEYVHGNLTAENVFVN 294
Cdd:pfam07714 109 LQIAK----GMEYLESKNFVHRDLAARNCLVS 136

Catalytic domain of the Serine/Threonine protein kinase, Vaccinia Related Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. VRKs were initially discovered due to its similarity to vaccinia virus B1R STK, which is important for viral replication. They play important roles in cell signaling, nuclear envelope dynamics, apoptosis, and stress responses. Vertebrates contain three VRK proteins (VRK1, VRK2, and VRK3) while invertebrates, specifically fruit flies and nematodes, seem to carry only a single ortholog. Mutations of VRK in Drosophila and Caenorhabditis elegans showed varying phenotypes ranging from embryonic lethality to mitotic and meiotic defects resulting in sterility. In vertebrates, VRK1 is implicated in cell cycle progression and proliferation, nuclear envelope assembly, and chromatin condensation. VRK2 is involved in modulating JNK signaling. VRK3 is an inactive pseudokinase that inhibits ERK signaling. The VRK 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 2469480083 134 GTELTDQNGKHWTLGALQIRDDQGILYEAEPTSavpSESRTQKWRFSLKLDSKD-GRLFNEQNFFQRVAKPLQVNKWKKQ 212
Cdd:cd14015     1 GEVLTDVTKRQWKLGKSIGQGGFGEIYLASDDS---TLSVGKDAKYVVKIEPHSnGPLFVEMNFYQRVAKPEMIKKWMKA 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 213 FLLPLLAIPTCIGFGIHQ---DKYRFLVFPSLGRSLQSALDDNPKhVVSERCVLQVACRLLDALEYLHENEYVHGNLTAE 289
Cdd:cd14015    78 KKLKHLGIPRYIGSGSHEykgEKYRFLVMPRFGRDLQKIFEKNGK-RFPEKTVLQLALRILDVLEYIHENGYVHADIKAS 156

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 290 NVFVNPE-DLSQVTLVGYGFTYRYCPGGKHVAYKEGSRSPHDGDLEFISMDLHKGCGPSRRSDLQTLGYCMLKWLYGSLP 368
Cdd:cd14015   157 NLLLGFGkNKDQVYLVDYGLASRYCPNGKHKEYKEDPRKAHNGTIEFTSRDAHKGVAPSRRGDLEILGYNMLQWLCGKLP 236

                         250       260       270
                  ....*....|....*....|....*....|....*..
gi 2469480083 369 WTNCLPNTEKITRQKQKYLDSPERLVGLCGRWNKASE 405
Cdd:cd14015   237 WEDNLKNPEYVQKQKEKYMDDIPLLLKKCFPGKDVPE 273

Catalytic domain of the Serine/Threonine protein kinase, Vaccinia Related Kinase 2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. VRKs were initially discovered due to its similarity to vaccinia virus B1R STK, which is important for viral replication. They play important roles in cell signaling, nuclear envelope dynamics, apoptosis, and stress responses. Vertebrates contain three VRK proteins. VRK2 exists as two alternative splice forms, A and B, which differ in their C-terminal regions. VRK2A, the predominant isoform, contains a hydrophobic tail and is anchored to the ER and mitochondria. It is expressed in all cell types. VRK2B lacks a membrane-anchor tail and is detected in the cytosol and the nucleus. Like VRK1, it can stabilize p53. VRK2B functionally replaces VRK1 in the nucleus of cell types where VRK1 is absent. VRK2 modulates hypoxia-induced stress responses by interacting with TAK1, an atypical MAPK kinase kinase which triggers cascades that activate JNK following oxidative stress. VRK2 also interacts with JIP1, a scaffold protein that assembles three consecutive members of a MAPK pathway. This interaction prevents the association of JNK with the signaling complex, leading to reduced phosphorylation and AP1-dependent transcription. The VRK2 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 2469480083 134 GTELTDQNGKHWTLGALQIRDDQGILYEAEPTSAVPSESRTqkwRFSLKLD-SKDGRLFNEQNFFQRVAKPLQVNKWKKQ 212
Cdd:cd14123     3 GCILTDTEKKNWRLGKMIGKGGFGLIYLASPQVNVPVEDDA---VHVIKVEyHENGPLFSELKFYQRAAKPDTISKWMKS 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 213 FLLPLLAIPTCIGFGIHQDK---YRFLVFPSLGRSLQSALDDNPKHVVSERcVLQVACRLLDALEYLHENEYVHGNLTAE 289
Cdd:cd14123    80 KQLDYLGIPTYWGSGLTEFNgtsYRFMVMDRLGTDLQKILIDNGGQFKKTT-VLQLGIRMLDVLEYIHENEYVHGDIKAA 158

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 290 NVFVNPEDLSQVTLVGYGFTYRYCPGGKHVAYKEGSRSPHDGDLEFISMDLHKGCGPSRRSDLQTLGYCMLKWLYGSLPW 369
Cdd:cd14123   159 NLLLGYRNPNEVYLADYGLSYRYCPNGNHKEYKENPRKGHNGTIEFTSLDAHKGVAPSRRGDLEILGYCMLHWLCGKLPW 238

                         250
                  ....*....|....*....
gi 2469480083 370 TNCLPNTEKITRQKQKYLD 388
Cdd:cd14123   239 EQNLKNPVAVQEAKAKLLS 257

Catalytic domain of the Serine/Threonine protein kinase, Casein Kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CK1 phosphorylates a variety of substrates including enzymes, transcription and splice factors, cytoskeletal proteins, viral oncogenes, receptors, and membrane-associated proteins. There are mutliple isoforms of CK1 and in mammals, seven isoforms (alpha, beta, gamma1-3, delta, and epsilon) have been characterized. These isoforms differ mainly in the length and structure of their C-terminal non-catalytic region. Some isoforms have several splice variants such as the long (L) and short (S) variants of CK1alpha. CK1 proteins are involved in the regulation of many cellular processes including membrane transport processes, circadian rhythm, cell division, apoptosis, and the development of cancer and neurodegenerative diseases. The CK1 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 2469480083 220 IPTCIGFGIHQDkYRFLVFPSLGRSLQSALDDNPKHVvSERCVLQVACRLLDALEYLHENEYVHGNLTAEN-VFVNPEDL 298
Cdd:cd14016    58 IPRLYWFGQEGD-YNVMVMDLLGPSLEDLFNKCGRKF-SLKTVLMLADQMISRLEYLHSKGYIHRDIKPENfLMGLGKNS 135

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 299 SQVTLVGYGFTYRYCPG--GKHVAYKEGSrsPHDGDLEFISMDLHKGCGPSRRSDLQTLGYCMLKWLYGSLPWTNcLPNT 376
Cdd:cd14016   136 NKVYLIDFGLAKKYRDPrtGKHIPYREGK--SLTGTARYASINAHLGIEQSRRDDLESLGYVLIYFLKGSLPWQG-LKAQ 212

                         170
                  ....*....|
gi 2469480083 377 EKitrqKQKY 386
Cdd:cd14016   213 SK----KEKY 218

Catalytic domain of the Serine/Threonine protein kinases, Casein Kinase 1 delta and epsilon; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CK1 phosphorylates a variety of substrates including enzymes, transcription and splice factors, cytoskeletal proteins, viral oncogenes, receptors, and membrane-associated proteins. There are mutliple isoforms of CK1 and in mammals, seven isoforms (alpha, beta, gamma1-3, delta, and epsilon) have been characterized. These isoforms differ mainly in the length and structure of their C-terminal non-catalytic region. The delta and epsilon isoforms of CK1 play important roles in circadian rhythm and cell growth. They phosphorylate PERIOD proteins (PER1-3), which are circadian clock proteins that fulfill negative regulatory functions. PER phosphorylation leads to its degradation. However, CRY proteins form a complex with PER and CK1delta/epsilon that protects PER from degradation and leads to nuclear accummulation of the complex, which inhibits BMAL1-CLOCK dependent transcription activation. CK1delta/epsilon also phosphorylate the tumor suppressor p53 and the cellular oncogene Mdm2, which are key regulators of cell growth, genome integrity, and the development of cancer. This subfamily also includes the CK1 fungal proteins Saccharomyces cerevisiae HRR25 and Schizosaccharomyces pombe HHP1. These fungal proteins are involved in DNA repair. The CK1 delta/epsilon 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 2469480083 214 LLPLLAIPTCIGFGIHQDkYRFLVFPSLGRSLQSALDD-NPKhvVSERCVLQVACRLLDALEYLHENEYVHGNLTAENVF 292
Cdd:cd14125    52 LQGGVGIPNVRWYGVEGD-YNVMVMDLLGPSLEDLFNFcSRK--FSLKTVLMLADQMISRIEYVHSKNFIHRDIKPDNFL 128

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 293 VN-PEDLSQVTLVGYGFT--YRYCPGGKHVAYKEGSRSphDGDLEFISMDLHKGCGPSRRSDLQTLGYCMLKWLYGSLPW 369
Cdd:cd14125   129 MGlGKKGNLVYIIDFGLAkkYRDPRTHQHIPYRENKNL--TGTARYASINTHLGIEQSRRDDLESLGYVLMYFNRGSLPW 206

                         170
                  ....*....|....*..
gi 2469480083 370 TNClpnteKITRQKQKY 386
Cdd:cd14125   207 QGL-----KAATKKQKY 218

Catalytic domain of the Serine/Threonine protein kinase, Casein Kinase 1 gamma; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CK1 phosphorylates a variety of substrates including enzymes, transcription and splice factors, cytoskeletal proteins, viral oncogenes, receptors, and membrane-associated proteins. There are mutliple isoforms of CK1 and in mammals, seven isoforms (alpha, beta, gamma1-3, delta, and epsilon) have been characterized. These isoforms differ mainly in the length and structure of their C-terminal non-catalytic region. CK1gamma proteins are unique within the CK1 subfamily in that they are palmitoylated at the C-termini and are anchored to the plasma membrane. CK1gamma is involved in transducing the signaling of LDL-receptor-related protein 6 (LRP6) through direct phosphorylation following Wnt stimulation, resulting in the recruitment of the scaffold protein Axin. In Xenopus embryos, CK1gamma is required during anterio-posterior patterning. In higher vertebrates, three CK1gamma (gamma1-3) isoforms exist. In mammalian cells, CK1gamma2 has been implicated in regulating the synthesis of sphingomyelin, a phospholipid that is found in the outer leaflet of the plasma membrane, by hyperphosphorylating and inactivating the ceramide transfer protein CERT. CK1gamma2 also phosphorylates the transcription factor Smad-3 resulting in its ubiquitination and degradation. It inhibits Smad-3 mediated responses of Transforming Growth Factor-beta (TGF-beta) including cell growth arrest. The CK1 gamma 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 2469480083 220 IPTCIGFGiHQDKYRFLVFPSLGRSLQSALDDNPKHVvSERCVLQVACRLLDALEYLHENEYVHGNLTAENVFVNPEDL- 298
Cdd:cd14126    58 LPQVYYFG-PCGKYNAMVLELLGPSLEDLFDLCDRTF-SLKTVLMIAIQLISRIEYVHSKHLIYRDVKPENFLIGRQSTk 135

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 299 --SQVTLVGYGFTYRY--CPGGKHVAYKEgsRSPHDGDLEFISMDLHKGCGPSRRSDLQTLGYCMLKWLYGSLPWTNCLP 374
Cdd:cd14126   136 kqHVIHIIDFGLAKEYidPETNKHIPYRE--HKSLTGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKA 213

                  ....*....
gi 2469480083 375 NTEKITRQK 383
Cdd:cd14126   214 DTLKERYQK 222

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 2469480083 242 GRSLQSALDDNPKHVvSERCVLQVACRLLDALEYLHENEYVHGNLTAENVFVNPEDlsQVTLVGYGFTYRYCPGGKHVAY 321
Cdd:cd00180    75 GGSLKDLLKENKGPL-SEEEALSILRQLLSALEYLHSNGIIHRDLKPENILLDSDG--TVKLADFGLAKDLDSDDSLLKT 151

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 2469480083 322 KEGSRSPhdgdlEFISMDLHKGCGPSRRSDLQTLGYCML 360
Cdd:cd00180   152 TGGTTPP-----YYAPPELLGGRYYGPKVDIWSLGVILY 185

Catalytic domain of the Serine/Threonine kinase, SH3 Binding Kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. SBK1, also called BSK146, is predominantly expressed in the brain. Its expression is increased in the developing brain during the late embryonic stage, coinciding with dramatic neuronal proliferation, migration, and maturation. SBK1 may play an important role in regulating brain development. The SBK1 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 2469480083 256 VVSERCVLQVACrlldALEYLHENEYVHGNLTAENVFVNPEDLSQVTLVGYGFTYRYcpgGKHVAYKEGSRSPHDGDLEf 335
Cdd:cd13987    91 ERVKRCAAQLAS----ALDFMHSKNLVHRDIKPENVLLFDKDCRRVKLCDFGLTRRV---GSTVKRVSGTIPYTAPEVC- 162

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2469480083 336 iSMDLHKG--CGPSrrSDLQTLG---YCMLKwlyGSLPWtnclpntEKITRQKQKY 386
Cdd:cd13987   163 -EAKKNEGfvVDPS--IDVWAFGvllFCCLT---GNFPW-------EKADSDDQFY 205

Catalytic domain of the Serine/Threonine protein kinase, Tau-Tubulin Kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. TTBK is a neuron-specific kinase that phosphorylates the microtubule-associated protein tau and promotes its aggregation. Higher vertebrates contain two TTBK proteins, TTBK1 and TTBK2, both of which have been implicated in neurodegeneration. Genetic variations in TTBK1 are linked to Alzheimer's disease (AD). Hyperphosphorylated tau is a major component of paired helical filaments that accumulate in the brain of AD patients. Studies in transgenic mice show that TTBK1 is involved in the phosphorylation-dependent pathogenic aggregation of tau. The TTBK1 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 2469480083 224 IGFGiHQDKYRFLVFPSLGRSLQSALDDNPKHVVSERCVLQVACRLLDALEYLHENEYVHGNLTAENVFVN--PEDLSQV 301
Cdd:cd14130    62 IGCG-RNEKFNYVVMQLQGRNLADLRRSQPRGTFTLSTTLRLGKQILESIEAIHSVGFLHRDIKPSNFAMGrlPSTYRKC 140

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 302 TLVGYGFTYRYCPGGKHVaykegsRSPHD-----GDLEFISMDLHKGCGPSRRSDLQTLGYCMLKWLYGSLPWTNcLPNT 376
Cdd:cd14130   141 YMLDFGLARQYTNTTGEV------RPPRNvagfrGTVRYASVNAHKNREMGRHDDLWSLFYMLVEFAVGQLPWRK-IKDK 213

                         170
                  ....*....|
gi 2469480083 377 EKITRQKQKY 386
Cdd:cd14130   214 EQVGMIKEKY 223

Catalytic domain of the Serine/Threonine Kinase, Mitogen-Activated Protein Kinase Kinase Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MAPKKKs (MKKKs or MAP3Ks) are also called MAP/ERK kinase kinases (MEKKs) in some cases. They phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. This subfamily is composed of the Apoptosis Signal-regulating Kinases ASK1 (or MAPKKK5) and ASK2 (or MAPKKK6), MEKK1, MEKK2, MEKK3, MEKK4, as well as plant and fungal MAPKKKs. Also included in this subfamily are the cell division control proteins Schizosaccharomyces pombe Cdc7 and Saccharomyces cerevisiae Cdc15. The MAPKKK 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 2469480083 220 IPTCIGFGIHQDKYR-FLVFPSlGRSLQSALDDNPKhvVSERCVLQVACRLLDALEYLHENEYVHGNLTAENVFVNPEDl 298
Cdd:cd06606    61 IVRYLGTERTENTLNiFLEYVP-GGSLASLLKKFGK--LPEPVVRKYTRQILEGLEYLHSNGIVHRDIKGANILVDSDG- 136

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 299 sQVTLVGYGF-----TYRYCPGGKHVAykeGS---RSPhdgdlEFISMDLHkgcgpSRRSDLQTLGYCMLKWLYGSLPWT 370
Cdd:cd06606   137 -VVKLADFGCakrlaEIATGEGTKSLR---GTpywMAP-----EVIRGEGY-----GRAADIWSLGCTVIEMATGKPPWS 202

                  ..
gi 2469480083 371 NC 372
Cdd:cd06606   203 EL 204

Catalytic domain of the Serine/Threonine protein kinase, Tau-Tubulin Kinase 2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. TTBK is a neuron-specific kinase that phosphorylates the microtubule-associated protein tau and promotes its aggregation. Higher vertebrates contain two TTBK proteins, TTBK1 and TTBK2, both of which have been implicated in neurodegeneration. Mutations in TTBK2 is associated with the development of spinocerebellar ataxia type 11, belonging to a group of neurodegenerative disorders characterized by progressive incoordination, dysarthria and impairment of eye movements. Brain tissues of SCA11 patients show the presence of neurofibrillary tangles and tau deposition in the brain, similar to Alzheimer's disease (AD) patients. The TTBK2 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 2469480083 224 IGFGiHQDKYRFLVFPSLGRSLQSALDDNPKHVVSERCVLQVACRLLDALEYLHENEYVHGNLTAENVFVN--PEDLSQV 301
Cdd:cd14129    62 IGCG-RNDRFNYVVMQLQGRNLADLRRSQSRGTFTISTTLRLGRQILESIESIHSVGFLHRDIKPSNFAMGrfPSTCRKC 140

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 302 TLVGYGFTYRY---CPGGKHVAYKEGSRsphdGDLEFISMDLHKGCGPSRRSDLQTLGYCMLKWLYGSLPWTNcLPNTEK 378
Cdd:cd14129   141 YMLDFGLARQFtnsCGDVRPPRAVAGFR----GTVRYASINAHRNREMGRHDDLWSLFYMLVEFVVGQLPWRK-IKDKEQ 215

                  ....*...
gi 2469480083 379 ITRQKQKY 386
Cdd:cd14129   216 VGSIKERY 223

Catalytic domain of the Protein Tyrosine Kinase, C-terminal Src kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Csk catalyzes the tyr phosphorylation of the regulatory C-terminal tail of Src kinases, resulting in their inactivation. Csk is expressed in a wide variety of tissues. As a negative regulator of Src, Csk plays a role in cell proliferation, survival, and differentiation, and consequently, in cancer development and progression. Csk is a cytoplasmic (or nonreceptor) PTK containing the Src homology domains, SH3 and SH2, N-terminal to the catalytic tyr kinase domain. To inhibit Src kinases, Csk is translocated to the membrane via binding to specific transmembrane proteins, G-proteins, or adaptor proteins near the membrane. In addition, Csk also shows Src-independent functions. It is a critical component in G-protein signaling, and plays a role in cytoskeletal reorganization and cell migration. The Csk subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 244 SLQSALDDNPKHVVSERCVLQVACRLLDALEYLHENEYVHGNLTAENVFVNPEDLSQVTlvGYGFTyrycpggkhvayKE 323
Cdd:cd05082    86 SLVDYLRSRGRSVLGGDCLLKFSLDVCEAMEYLEGNNFVHRDLAARNVLVSEDNVAKVS--DFGLT------------KE 151

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2469480083 324 GSRSPHDGDL--EFISMDLHKGCGPSRRSDLQTLGycMLKW---LYGSLPWTNcLPNTEKITRQKQKY-LDSPE 391
Cdd:cd05082   152 ASSTQDTGKLpvKWTAPEALREKKFSTKSDVWSFG--ILLWeiySFGRVPYPR-IPLKDVVPRVEKGYkMDAPD 222

Catalytic domain of the Dual-specificity protein kinases, CDC-like 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. CLKs are involved in the phosphorylation and regulation of serine/arginine-rich (SR) proteins, which play a crucial role in pre-mRNA splicing by directing splice site selection. SR proteins are phosphorylated first by SR protein kinases (SRPKs) at the N-terminus, which leads to its assembly into nuclear speckles where splicing factors are stored. CLKs phosphorylate the C-terminal part of SR proteins, causing the nuclear speckles to dissolve and splicing factors to be recruited at sites of active transcription. Based on a conserved "EHLAMMERILG" signature motif which may be crucial for substrate specificity, CLKs are also referred to as LAMMER kinases. CLKs autophosphorylate at tyrosine residues and phosphorylate their substrates exclusively on S/T residues. In Drosophila, the CLK homolog DOA (Darkener of apricot) is essential for embryogenesis and its mutation leads to defects in sexual differentiation, eye formation, and neuronal development. In fission yeast, the CLK homolog Lkh1 is a negative regulator of filamentous growth and asexual flocculation, and is also involved in oxidative stress response. Vertebrates contain mutliple CLK proteins and mammals have four (CLK1-4). The CLK 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2469480083 235 FLVFPSLGRSLQSALDDNPKHVVSERCVLQVACRLLDALEYLHENEYVHGNLTAENV-FVNpEDLSQVTLVGYGFTYRY 312
Cdd:cd14134    90 CIVFELLGPSLYDFLKKNNYGPFPLEHVQHIAKQLLEAVAFLHDLKLTHTDLKPENIlLVD-SDYVKVYNPKKKRQIRV 167

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

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2469480083  226 FGIHQDK-YRFLVFPSL-GRSLQSALDDNPKhvVSERCVLQVACRLLDALEYLHENEYVHGNLTAENVFVN 294
Cdd:smart00220  63 YDVFEDEdKLYLVMEYCeGGDLFDLLKKRGR--LSEDEARFYLRQILSALEYLHSKGIVHRDLKPENILLD 131

Catalytic (repeat 2) domain of the Protein Tyrosine Kinase, Tyrosine kinase 2; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Tyk2 is widely expressed in many tissues. It is involved in signaling via the cytokine receptors IFN-alphabeta, IL-6, IL-10, IL-12, IL-13, and IL-23. It mediates cell surface urokinase receptor (uPAR) signaling and plays a role in modulating vascular smooth muscle cell (VSMC) functional behavior in response to injury. Tyk2 is also important in dendritic cell function and T helper (Th)1 cell differentiation. A homozygous mutation of Tyk2 was found in a patient with hyper-IgE syndrome (HIES), a primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and elevated serum IgE. This suggests that Tyk2 may play important roles in multiple cytokine signaling involved in innate and adaptive immunity. Tyk2 is a member of the Janus kinase (Jak) subfamily of proteins, which are cytoplasmic (or nonreceptor) PTKs containing an N-terminal FERM domain, followed by a Src homology 2 (SH2) domain, a pseudokinase domain, and a C-terminal tyr kinase catalytic domain. Jaks are crucial for cytokine receptor signaling. They are activated by autophosphorylation upon cytokine-induced receptor aggregation, and subsequently trigger downstream signaling events such as the phosphorylation of signal transducers and activators of transcription (STATs). The Tyk2 subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 245 LQSALDDNPKHVVSERCVLQVACRLLDALEYLHENEYVHGNLTAENVFVNPEDLsqVTLVGYGFTYRYCPGGKHVAYKEG 324
Cdd:cd05080    92 LGSLRDYLPKHSIGLAQLLLFAQQICEGMAYLHSQHYIHRDLAARNVLLDNDRL--VKIGDFGLAKAVPEGHEYYRVRED 169

                  ....
gi 2469480083 325 SRSP 328
Cdd:cd05080   170 GDSP 173

Catalytic domain of the Serine/Threonine Kinase, Phosphorylase kinase Gamma 1 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 1 subunit (PhKG1) is also referred to as the muscle gamma isoform. 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 PhKG1 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 2469480083 235 FLVFPSLGR-SLQSALDDnpKHVVSERCVLQVACRLLDALEYLHENEYVHGNLTAENVFVnpEDLSQVTLVGYGFTYRYC 313
Cdd:cd14182    86 FLVFDLMKKgELFDYLTE--KVTLSEKETRKIMRALLEVICALHKLNIVHRDLKPENILL--DDDMNIKLTDFGFSCQLD 161

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 2469480083 314 PGGKhvaYKEGSRSPHDGDLEFI--SMD-LHKGCGpsRRSDLQTLGYCMLKWLYGSLPW 369
Cdd:cd14182   162 PGEK---LREVCGTPGYLAPEIIecSMDdNHPGYG--KEVDMWSTGVIMYTLLAGSPPF 215

Catalytic domain of the Serine/Threonine kinase, Interleukin-1 Receptor Associated Kinase 2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. IRAKs are involved in Toll-like receptor (TLR) and interleukin-1 (IL-1) signalling pathways, and are thus critical in regulating innate immune responses and inflammation. IRAKs contain an N-terminal Death domain (DD), a proST region (rich in serines, prolines, and threonines), a central kinase domain, and a C-terminal domain; IRAK-4 lacks the C-terminal domain. Vertebrates contain four IRAKs (IRAK-1, -2, -3 (or -M), and -4) that display distinct functions and patterns of expression and subcellular distribution, and can differentially mediate TLR signaling. IRAK2 plays a role in mediating NFkB activation by TLR3, TLR4, and TLR8. It is specifically targeted by the viral protein A52, which is important for virulence, to inhibit all IL-1/TLR pathways, indicating that IRAK2 has a predominant role in NFkB activation. It is redundant with IRAK1 in early signaling but is critical for late and sustained activation. The IRAK2 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 2469480083 214 LLPLLAIptCIGFGIHQDKYRFLVFPSLGRSLQSALDDNPkhvVSERCVLQVACRLLDALEYLHENEYVHGNLTAENVFV 293
Cdd:cd14157    54 ILPLLGF--CVESDCHCLIYPYMPNGSLQDRLQQQGGSHP---LPWEQRLSISLGLLKAVQHLHNFGILHGNIKSSNVLL 128

                          90       100
                  ....*....|....*....|....*...
gi 2469480083 294 NPEDLSQVTLVGygftYRYCPGGKHVAY 321
Cdd:cd14157   129 DGNLLPKLGHSG----LRLCPVDKKSVY 152

Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 4; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MEKK4 is a MAPK kinase kinase that phosphorylates and activates the c-Jun N-terminal kinase (JNK) and p38 MAPK signaling pathways by directly activating their respective MAPKKs, MKK4/MKK7 and MKK3/MKK6. JNK and p38 are collectively known as stress-activated MAPKs, as they are activated in response to a variety of environmental stresses and pro-inflammatory cytokines. MEKK4 also plays roles in the re-polarization of the actin cytoskeleton in response to osmotic stress, in the proper closure of the neural tube, in cardiovascular development, and in immune responses. The MEKK4 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 2469480083 220 IPTCIGFGIHQDK-YRFLVFPSLGrSLQSALDDNpkHVVSERCVLQVACRLLDALEYLHENEYVHGNLTAENVFVNpeDL 298
Cdd:cd06626    61 LVRYYGVEVHREEvYIFMEYCQEG-TLEELLRHG--RILDEAVIRVYTLQLLEGLAYLHENGIVHRDIKPANIFLD--SN 135

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2469480083 299 SQVTLVGYGFTYRYCPGGKHVAYKEGSR--------SPhdgdlEFISMDLHKGCGpsRRSDLQTLGYCMLKWLYGSLPWT 370
Cdd:cd06626   136 GLIKLGDFGSAVKLKNNTTTMAPGEVNSlvgtpaymAP-----EVITGNKGEGHG--RAADIWSLGCVVLEMATGKRPWS 208

                  ..
gi 2469480083 371 NC 372
Cdd:cd06626   209 EL 210

Catalytic domain of the Serine/Threonine kinase, Protein Kinase D; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PKDs are important regulators of many intracellular signaling pathways such as ERK and JNK, and cellular processes including the organization of the trans-Golgi network, membrane trafficking, cell proliferation, migration, and apoptosis. They contain N-terminal cysteine-rich zinc binding C1 (PKC conserved region 1), central PH (Pleckstrin Homology), and C-terminal catalytic kinase domains. Mammals harbor three types of PKDs: PKD1 (or PKCmu), PKD2, and PKD3 (or PKCnu). PKDs are activated in a PKC-dependent manner by many agents including diacylglycerol (DAG), PDGF, neuropeptides, oxidative stress, and tumor-promoting phorbol esters, among others. The PKD 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
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 2469480083 253 PKHVVSERCVLQVACRLLDALEYLHENEYVHGNLTAENVFVN-PEDLSQVTLVGYGF 308
Cdd:cd14082    96 EKGRLPERITKFLVTQILVALRYLHSKNIVHCDLKPENVLLAsAEPFPQVKLCDFGF 152

Catalytic domain of the Serine/Threonine Kinase, Yeast Sps1/Ste20-related Kinase 4; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. YSK4 is a putative MAPKKK, whose mammalian gene has been isolated. MAPKKKs phosphorylate and activate MAPK kinases, which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. The YSK4 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 2469480083 265 VACR----LLDALEYLHENEYVHGNLTAENVFVNPEdlSQVTLVGYGFTYRYCPGGKHVAYKEGSRSPHdGDLEFISMDL 340
Cdd:cd06631   104 VFCRytkqILEGVAYLHNNNVIHRDIKGNNIMLMPN--GVIKLIDFGCAKRLCINLSSGSQSQLLKSMR-GTPYWMAPEV 180