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 530425127  15 GKNLYTNEYVAIKLEPIKSRAPQLHLEYRFYKQLSATEGVPQVYYFGPCGKYNAMVLELLGPSLEDLFDLCDRTFTLKTV 94
Cdd:cd14126   19 GKNLYNNEHVAIKLEPMKSRAPQLHLEYRFYKLLGQAEGLPQVYYFGPCGKYNAMVLELLGPSLEDLFDLCDRTFSLKTV 98

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127  95 LMIAIQLITRMEYVHTKSLIYRDVKPENFLVGRPGTKRQHAIHIIDFGLAKEYIDPETKKHIPYREHKSLTGTARYMSIN 174
Cdd:cd14126   99 LMIAIQLISRIEYVHSKHLIYRDVKPENFLIGRQSTKKQHVIHIIDFGLAKEYIDPETNKHIPYREHKSLTGTARYMSIN 178

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127 175 THLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPIEVLCENFPEEMATYLRYVRRLDFFEK 254
Cdd:cd14126  179 THLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPIEVLCENFPEEMATYLRYVRRLDFFET 258

                        250       260       270
                 ....*....|....*....|....*....|
gi 530425127 255 PDYDYLRKLFTDLFDRSGFVFDYEYDWAGK 284
Cdd:cd14126  259 PDYDYLRKLFTDLFDRKGYTDDYEFDWTGK 288

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 530425127  15 GKNLYTNEYVAIKLEPIKSRAPQLHLEYRFYKQLSATEGVPQVYYFGPCGKYNAMVLELLGPSLEDLFDLCDRTFTLKTV 94
Cdd:cd14126   19 GKNLYNNEHVAIKLEPMKSRAPQLHLEYRFYKLLGQAEGLPQVYYFGPCGKYNAMVLELLGPSLEDLFDLCDRTFSLKTV 98

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127  95 LMIAIQLITRMEYVHTKSLIYRDVKPENFLVGRPGTKRQHAIHIIDFGLAKEYIDPETKKHIPYREHKSLTGTARYMSIN 174
Cdd:cd14126   99 LMIAIQLISRIEYVHSKHLIYRDVKPENFLIGRQSTKKQHVIHIIDFGLAKEYIDPETNKHIPYREHKSLTGTARYMSIN 178

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127 175 THLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPIEVLCENFPEEMATYLRYVRRLDFFEK 254
Cdd:cd14126  179 THLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPIEVLCENFPEEMATYLRYVRRLDFFET 258

                        250       260       270
                 ....*....|....*....|....*....|
gi 530425127 255 PDYDYLRKLFTDLFDRSGFVFDYEYDWAGK 284
Cdd:cd14126  259 PDYDYLRKLFTDLFDRKGYTDDYEFDWTGK 288

Serine/threonine protein kinase [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127  15 GKNLYTNEYVAIK-LEPIKSRAPQ----LHLEYRFYKQLSAtEGVPQVYYFGPCGKYNAMVLELL-GPSLEDLFDLcDRT 88
Cdd:COG0515   26 ARDLRLGRPVALKvLRPELAADPEarerFRREARALARLNH-PNIVRVYDVGEEDGRPYLVMEYVeGESLADLLRR-RGP 103

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127  89 FTLKTVLMIAIQLITRMEYVHTKSLIYRDVKPENFLVGRPGTkrqhaIHIIDFGLAKEYIDPETKkhipyrEHKSLTGTA 168
Cdd:COG0515  104 LPPAEALRILAQLAEALAAAHAAGIVHRDIKPANILLTPDGR-----VKLIDFGIARALGGATLT------QTGTVVGTP 172

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 530425127 169 RYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGlkaDTLKERYQKIGdTKRATPIEVLCENFPEEMA 240
Cdd:COG0515  173 GYMAPEQARGEPVDPRSDVYSLGVTLYELLTGRPPFDG---DSPAELLRAHL-REPPPPPSELRPDLPPALD 240

Casein kinase 1 gamma C terminal; This domain family is found in eukaryotes, and is typically between 54 and 99 amino acids in length. The family is found in association with pfam00069. CK1gamma is a membrane-bound member of the CK1 family. Gain-of-function and loss-of-function experiments show that CK1gamma is both necessary and sufficient to transduce LRP6 signalling in vertebrates and Drosophila cells.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127  284 KPLPTPIGTVHTDLPSQPQLRDKTQPHSK-----------NQVRPGR-----DRPPQGGAWAASVTPYCPH----QALNS 343
Cdd:pfam12605   1 KPMPTPVGSLQTSESAVSPSREAHIGVSRpplpqprrvsqQGSKGRKgawppPTPQTNAETLGSHLPADRHggsvQVVSS 80

                          90
                  ....*....|....*....
gi 530425127  344 TNGELNADDPTAGHSNAPI 362
Cdd:pfam12605  81 TNGELNTDDPTAGHSNAPI 99

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 530425127   24 VAIKLepIKSRAPQLHL-----EYRFYKQLSaTEGVPQVYYFGPCGKYNAMVLELL-GPSLEDLFDLCDRTFTLKTVLMI 97
Cdd:pfam07714  31 VAVKT--LKEGADEEERedfleEASIMKKLD-HPNIVKLLGVCTQGEPLYIVTEYMpGGDLLDFLRKHKRKLTLKDLLSM 107

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 530425127   98 AIQLITRMEYVHTKSLIYRDVKPENFLVGRPGTkrqhaIHIIDFGLAKE-YIDPETKKH 155
Cdd:pfam07714 108 ALQIAKGMEYLESKNFVHRDLAARNCLVSENLV-----VKISDFGLSRDiYDDDYYRKR 161

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 530425127  15 GKNLYTNEYVAIKLEPIKSRAPQLHLEYRFYKQLSATEGVPQVYYFGPCGKYNAMVLELLGPSLEDLFDLCDRTFTLKTV 94
Cdd:cd14126   19 GKNLYNNEHVAIKLEPMKSRAPQLHLEYRFYKLLGQAEGLPQVYYFGPCGKYNAMVLELLGPSLEDLFDLCDRTFSLKTV 98

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127  95 LMIAIQLITRMEYVHTKSLIYRDVKPENFLVGRPGTKRQHAIHIIDFGLAKEYIDPETKKHIPYREHKSLTGTARYMSIN 174
Cdd:cd14126   99 LMIAIQLISRIEYVHSKHLIYRDVKPENFLIGRQSTKKQHVIHIIDFGLAKEYIDPETNKHIPYREHKSLTGTARYMSIN 178

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127 175 THLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPIEVLCENFPEEMATYLRYVRRLDFFEK 254
Cdd:cd14126  179 THLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPIEVLCENFPEEMATYLRYVRRLDFFET 258

                        250       260       270
                 ....*....|....*....|....*....|
gi 530425127 255 PDYDYLRKLFTDLFDRSGFVFDYEYDWAGK 284
Cdd:cd14126  259 PDYDYLRKLFTDLFDRKGYTDDYEFDWTGK 288

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 530425127  15 GKNLYTNEYVAIKLEPIKSRAPQLHLEYRFYKQLSATEGVPQVYYFGPCGKYNAMVLELLGPSLEDLFDLCDRTFTLKTV 94
Cdd:cd14125   19 GTNIQTGEEVAIKLESVKTKHPQLLYESKLYKILQGGVGIPNVRWYGVEGDYNVMVMDLLGPSLEDLFNFCSRKFSLKTV 98

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127  95 LMIAIQLITRMEYVHTKSLIYRDVKPENFLVGRpgTKRQHAIHIIDFGLAKEYIDPETKKHIPYREHKSLTGTARYMSIN 174
Cdd:cd14125   99 LMLADQMISRIEYVHSKNFIHRDIKPDNFLMGL--GKKGNLVYIIDFGLAKKYRDPRTHQHIPYRENKNLTGTARYASIN 176

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127 175 THLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPIEVLCENFPEEMATYLRYVRRLDFFEK 254
Cdd:cd14125  177 THLGIEQSRRDDLESLGYVLMYFNRGSLPWQGLKAATKKQKYEKISEKKMSTPIEVLCKGFPSEFATYLNYCRSLRFDDK 256

                        250
                 ....*....|....*....
gi 530425127 255 PDYDYLRKLFTDLFDRSGF 273
Cdd:cd14125  257 PDYSYLRRLFRDLFHREGF 275

Catalytic domain of the Serine/Threonine protein kinases, Casein Kinase 1 alpha; 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. CK1alpha plays a role in cell cycle progression, spindle dynamics, and chromosome segregation. It is also involved in regulating apoptosis mediated by Fas or the retinoid X receptor (RXR), and is a positive regulator of Wnt signaling. CK1alpha phosphorylates the NS5A protein of flaviviruses such as the Hepatitis C virus (HCV) and yellow fever virus (YFV), and influences flaviviral replication. The CK1 alpha 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 530425127  15 GKNLYTNEYVAIKLEPIKSRAPQLHLEYRFYKQLSATEGVPQVYYFGPCGKYNAMVLELLGPSLEDLFDLCDRTFTLKTV 94
Cdd:cd14128   19 GINITNGEEVAVKLESQKARHPQLLYESKLYKILQGGVGIPHIRWYGQEKDYNVLVMDLLGPSLEDLFNFCSRRFTMKTV 98

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127  95 LMIAIQLITRMEYVHTKSLIYRDVKPENFL--VGRPGTKrqhaIHIIDFGLAKEYIDPETKKHIPYREHKSLTGTARYMS 172
Cdd:cd14128   99 LMLADQMIGRIEYVHNKNFIHRDIKPDNFLmgIGRHCNK----LFLIDFGLAKKYRDSRTRQHIPYREDKNLTGTARYAS 174

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127 173 INTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPIEVLCENFPEEMATYLRYVRRLDFF 252
Cdd:cd14128  175 INAHLGIEQSRRDDMESLGYVLMYFNRGSLPWQGLKAATKKQKYEKISEKKMSTPVEVLCKGFPAEFAMYLNYCRGLRFE 254

                        250
                 ....*....|..
gi 530425127 253 EKPDYDYLRKLF 264
Cdd:cd14128  255 EAPDYMYLRQLF 266

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 530425127  22 EYVaIKLEPiKSRAPqLHLEYRFY----KQLSATE----------GVPQVYYFG----PCGKYNAMVLELLGPSLEDLFD 83
Cdd:cd14015   42 KYV-VKIEP-HSNGP-LFVEMNFYqrvaKPEMIKKwmkakklkhlGIPRYIGSGsheyKGEKYRFLVMPRFGRDLQKIFE 118

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127  84 LCDRTFTLKTVLMIAIQLITRMEYVHTKSLIYRDVKPENFLVGrpGTKRQHAIHIIDFGLAKEYIDpeTKKHIPYRE--H 161
Cdd:cd14015  119 KNGKRFPEKTVLQLALRILDVLEYIHENGYVHADIKASNLLLG--FGKNKDQVYLVDYGLASRYCP--NGKHKEYKEdpR 194

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127 162 KSLTGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIgdtKRATPIEVL---C---ENF 235
Cdd:cd14015  195 KAHNGTIEFTSRDAHKGVAPSRRGDLEILGYNMLQWLCGKLPWEDNLKNPEYVQKQKE---KYMDDIPLLlkkCfpgKDV 271

                        250       260
                 ....*....|....*....|....*....
gi 530425127 236 PEEMATYLRYVRRLDFFEKPDYDYLRKLF 264
Cdd:cd14015  272 PEELQKYLKYVASLEYEEKPDYEKLRKIL 300

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 530425127  17 NLYTNEYVAIKLEPIKSRAPQLHLEYRFYKQLSATEGVPQVYYFGPCGKYNAMVLELLGPSLEDLFDLCDR-TFTLKTVL 95
Cdd:cd14130   21 DLLTRENVALKVESAQQPKQVLKMEVAVLKKLQGKDHVCRFIGCGRNEKFNYVVMQLQGRNLADLRRSQPRgTFTLSTTL 100

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127  96 MIAIQLITRMEYVHTKSLIYRDVKPENFLVGR-PGTKRQhaIHIIDFGLAKEYIDpETKKHIPYREHKSLTGTARYMSIN 174
Cdd:cd14130  101 RLGKQILESIEAIHSVGFLHRDIKPSNFAMGRlPSTYRK--CYMLDFGLARQYTN-TTGEVRPPRNVAGFRGTVRYASVN 177

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127 175 THLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADtlkeryQKIGDTKRATPIEVLCENFPEEMATYLRYVRRLDFFEK 254
Cdd:cd14130  178 AHKNREMGRHDDLWSLFYMLVEFAVGQLPWRKIKDK------EQVGMIKEKYEHRMLLKHMPSEFHLFLDHIASLDYFTK 251

                        250
                 ....*....|
gi 530425127 255 PDYDYLRKLF 264
Cdd:cd14130  252 PDYQLIMSVF 261

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 530425127  15 GKNLYTNEYVAIKLEPIKSRAPQLHL---EYRFYKQLSaTEGVPQVYYFGPCGKYNAMVLELL-GPSLEDLFDLCDRTFT 90
Cdd:cd00180   12 ARDKETGKKVAVKVIPKEKLKKLLEEllrEIEILKKLN-HPNIVKLYDVFETENFLYLVMEYCeGGSLKDLLKENKGPLS 90

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127  91 LKTVLMIAIQLITRMEYVHTKSLIYRDVKPENFLVGRPGTkrqhaIHIIDFGLAKEYIDPETKKHIPYRehkslTGTARY 170
Cdd:cd00180   91 EEEALSILRQLLSALEYLHSNGIIHRDLKPENILLDSDGT-----VKLADFGLAKDLDSDDSLLKTTGG-----TTPPYY 160

                        170       180
                 ....*....|....*....|....*..
gi 530425127 171 MSINTHLGKEQSRRDDLEALGHMFMYF 197
Cdd:cd00180  161 APPELLGGRYYGPKVDIWSLGVILYEL 187

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 530425127  65 KYNAMVLELLGPSLEDLFDLCDRTFTLKTVLMIAIQLITRMEYVHTKSLIYRDVKPENFLVGrpgTKRQHAIHIIDFGLA 144
Cdd:cd14123  102 SYRFMVMDRLGTDLQKILIDNGGQFKKTTVLQLGIRMLDVLEYIHENEYVHGDIKAANLLLG---YRNPNEVYLADYGLS 178

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127 145 KEYIdpETKKHIPYREH--KSLTGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPW----------QGLKADTL 212
Cdd:cd14123  179 YRYC--PNGNHKEYKENprKGHNGTIEFTSLDAHKGVAPSRRGDLEILGYCMLHWLCGKLPWeqnlknpvavQEAKAKLL 256

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|...
gi 530425127 213 KERYQKIgdTKRATPIEVLCenfpeEMATYLRYVRRLDFFEKPDYDYLRKLFT 265
Cdd:cd14123  257 SNLPDSV--LKWSTGGSSSM-----EIAQFLSRVKDLAYDEKPDYQALKKILS 302

Serine/threonine protein kinase [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127  15 GKNLYTNEYVAIK-LEPIKSRAPQ----LHLEYRFYKQLSAtEGVPQVYYFGPCGKYNAMVLELL-GPSLEDLFDLcDRT 88
Cdd:COG0515   26 ARDLRLGRPVALKvLRPELAADPEarerFRREARALARLNH-PNIVRVYDVGEEDGRPYLVMEYVeGESLADLLRR-RGP 103

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127  89 FTLKTVLMIAIQLITRMEYVHTKSLIYRDVKPENFLVGRPGTkrqhaIHIIDFGLAKEYIDPETKkhipyrEHKSLTGTA 168
Cdd:COG0515  104 LPPAEALRILAQLAEALAAAHAAGIVHRDIKPANILLTPDGR-----VKLIDFGIARALGGATLT------QTGTVVGTP 172

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 530425127 169 RYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGlkaDTLKERYQKIGdTKRATPIEVLCENFPEEMA 240
Cdd:COG0515  173 GYMAPEQARGEPVDPRSDVYSLGVTLYELLTGRPPFDG---DSPAELLRAHL-REPPPPPSELRPDLPPALD 240

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127    15 GKNLYTNEYVAIK---LEPIKSRAPQLHLEYRFYKQLSaTEGVPQVYYFGPCGKYNAMVLELLgpSLEDLFDLCDR--TF 89
Cdd:smart00220  18 ARDKKTGKLVAIKvikKKKIKKDRERILREIKILKKLK-HPNIVRLYDVFEDEDKLYLVMEYC--EGGDLFDLLKKrgRL 94

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127    90 TLKTVLMIAIQLITRMEYVHTKSLIYRDVKPENFLVGRPGTkrqhaIHIIDFGLAKEYIDPETkkhipyreHKSLTGTAR 169
Cdd:smart00220  95 SEDEARFYLRQILSALEYLHSKGIVHRDLKPENILLDEDGH-----VKLADFGLARQLDPGEK--------LTTFVGTPE 161

                          170       180       190       200       210       220
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 530425127   170 YMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGlkADTLKERYQKIGDTKRATPIEVlcENFPEE 238
Cdd:smart00220 162 YMAPEVLLGKGYGKAVDIWSLGVILYELLTGKPPFPG--DDQLLELFKKIGKPKPPFPPPE--WDISPE 226

Catalytic domain of AGC family Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. AGC kinases regulate many cellular processes including division, growth, survival, metabolism, motility, and differentiation. Many are implicated in the development of various human diseases. Members of this family include cAMP-dependent Protein Kinase (PKA), cGMP-dependent Protein Kinase (PKG), Protein Kinase C (PKC), Protein Kinase B (PKB), G protein-coupled Receptor Kinase (GRK), Serum- and Glucocorticoid-induced Kinase (SGK), and 70 kDa ribosomal Protein S6 Kinase (p70S6K or S6K), among others. AGC kinases share an activation mechanism based on the phosphorylation of up to three sites: the activation loop (A-loop), the hydrophobic motif (HM) and the turn motif. Phosphorylation at the A-loop is required of most AGC kinases, which results in a disorder-to-order transition of the A-loop. The ordered conformation results in the access of substrates and ATP to the active site. A subset of AGC kinases with C-terminal extensions containing the HM also requires phosphorylation at this site. Phosphorylation at the HM allows the C-terminal extension to form an ordered structure that packs into the hydrophobic pocket of the catalytic domain, which then reconfigures the kinase into an active bi-lobed state. In addition, growth factor-activated AGC kinases such as PKB, p70S6K, RSK, MSK, PKC, and SGK, require phosphorylation at the turn motif (also called tail or zipper site), located N-terminal to the HM at the C-terminal extension. The AGC family 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 530425127  69 MVLELL--GpsleDLFDLCDR--TFTLKTVLMIAIQLITRMEYVHTKSLIYRDVKPENFLVGRPGtkrqHaIHIIDFGLA 144
Cdd:cd05123   70 LVLDYVpgG----ELFSHLSKegRFPEERARFYAAEIVLALEYLHSLGIIYRDLKPENILLDSDG----H-IKLTDFGLA 140

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 530425127 145 KEYIDPETKKHipyrehkSLTGTARYMSINTHLGKEQSRRDDLEALGHMfMY-FLRGSLPWQglkADTLKERYQKI 219
Cdd:cd05123  141 KELSSDGDRTY-------TFCGTPEYLAPEVLLGKGYGKAVDWWSLGVL-LYeMLTGKPPFY---AENRKEIYEKI 205

Catalytic domain of the Serine/Threonine Kinase, Phosphoinositide-dependent kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PDK1 carries an N-terminal catalytic domain and a C-terminal pleckstrin homology (PH) domain that binds phosphoinositides. It phosphorylates the activation loop of AGC kinases that are regulated by PI3K such as PKB, SGK, and PKC, among others, and is crucial for their activation. Thus, it contributes in regulating many processes including metabolism, growth, proliferation, and survival. PDK1 also has the ability to autophosphorylate and is constitutively active in mammalian cells. It is essential for normal embryo development and is important in regulating cell volume. The PDK1 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 530425127  69 MVLELL--GPSLEDLFDLcdRTFTLKTVLMIAIQLITRMEYVHTKSLIYRDVKPENFLVgrpgTKRQHaIHIIDFGLAK- 145
Cdd:cd05581   78 FVLEYApnGDLLEYIRKY--GSLDEKCTRFYTAEIVLALEYLHSKGIIHRDLKPENILL----DEDMH-IKITDFGTAKv 150

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127 146 ---------EYIDPETKKHIPYREHKSLTGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGlkaDTLKERY 216
Cdd:cd05581  151 lgpdsspesTKGDADSQIAYNQARAASFVGTAEYVSPELLNEKPAGKSSDLWALGCIIYQMLTGKPPFRG---SNEYLTF 227

                        170       180
                 ....*....|....*....|.
gi 530425127 217 QKIgdTKRATPIevlCENFPE 237
Cdd:cd05581  228 QKI--VKLEYEF---PENFPP 243

Catalytic domain of PRKX-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 human PRKX (X chromosome-encoded protein kinase), Drosophila DC2, and similar proteins. PRKX is present in many tissues including fetal and adult brain, kidney, and lung. The PRKX gene is located in the Xp22.3 subregion and has a homolog called PRKY on the Y chromosome. An abnormal interchange between PRKX aand PRKY leads to the sex reversal disorder of XX males and XY females. PRKX is implicated in granulocyte/macrophage lineage differentiation, renal cell epithelial migration, and tubular morphogenesis in the developing kidney. The PRKX-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 530425127  87 RTFTLKTVLMIAIQLITRMEYVHTKSLIYRDVKPENFLVGRPGtkrqHaIHIIDFGLAKEYIDpetkkhipyrEHKSLTG 166
Cdd:cd05612   96 GRFSNSTGLFYASEIVCALEYLHSKEIVYRDLKPENILLDKEG----H-IKLTDFGFAKKLRD----------RTWTLCG 160

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127 167 TARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGlkaDTLKERYQKIgdtkratpievlcenfpeeMATYLRYV 246
Cdd:cd05612  161 TPEYLAPEVIQSKGHNKAVDWWALGILIYEMLVGYPPFFD---DNPFGIYEKI-------------------LAGKLEFP 218

                        170
                 ....*....|....*..
gi 530425127 247 RRLDFFEKpdyDYLRKL 263
Cdd:cd05612  219 RHLDLYAK---DLIKKL 232

Catalytic domain of Mitogen-Activated Protein Kinase (MAPK) Kinase Kinase-like Serine/Threonine kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed mainly of MAP3Ks and similar proteins, including TGF-beta Activated Kinase-1 (TAK1, also called MAP3K7), MAP3K12, MAP3K13, Mixed lineage kinase (MLK), MLK-Like mitogen-activated protein Triple Kinase (MLTK), and Raf (Rapidly Accelerated Fibrosarcoma) kinases. MAP3Ks (MKKKs or MAPKKKs) 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. Also included in this subfamily is the pseudokinase Kinase Suppressor of Ras (KSR), which is a scaffold protein that functions downstream of Ras and upstream of Raf in the Extracellular signal-Regulated Kinase (ERK) pathway.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530425127  59 YFGPC--GKYNAMVLELL-GPSLEDLFDLCDRTFTLKTVLMIAIQlITR-MEYVHTKSLIYRDVKPENFLVGRPGTkrqh 134
Cdd:cd13999   55 FIGAClsPPPLCIVTEYMpGGSLYDLLHKKKIPLSWSLRLKIALD-IARgMNYLHSPPIIHRDLKSLNILLDENFT---- 129

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 530425127 135 aIHIIDFGLAKEYIDPETKKhipyrehKSLTGTARYMS 172
Cdd:cd13999  130 -VKIADFGLSRIKNSTTEKM-------TGVVGTPRWMA 159