Protein Kinases, catalytic domain; The protein kinase superfamily is mainly composed of the catalytic domains of serine/threonine-specific and tyrosine-specific protein kinases. It also includes RIO kinases, which are atypical serine protein kinases, aminoglycoside phosphotransferases, and choline kinases. These proteins catalyze the transfer of the gamma-phosphoryl group from ATP to hydroxyl groups in specific substrates such as serine, threonine, or tyrosine residues of proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIQTASRRQTFFDSKGFPKNITNNRGKKRYPDSKDLTMVL 80
Cdd:cd14225  228 MWSLGCILAELYTGYPLFPGENEVEQLACIMEVLGLPPPELIENAQRRRLFFDSKGNPRCITNSKGKKRRPNSKDLASAL 307

                         90       100       110
                 ....*....|....*....|....*....|....
gi 537361024  81 KTYDTSFLDFLRRCLVWEPSLRMTPDQALKHAWI 114
Cdd:cd14225  308 KTSDPLFLDFIRRCLEWDPSKRMTPDEALQHEWI 341

Catalytic domain of the protein kinase, Dual-specificity tYrosine-phosphorylated and -Regulated Kinase 4; 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. DYRK4 is a testis-specific kinase with restricted expression to postmeiotic spermatids. It may function during spermiogenesis, however, it is not required for male fertility. DYRK4 has also been detected in a human teratocarcinoma cell line induced to produce postmitotic neurons. It may have a role in neuronal differentiation. DYRKs autophosphorylate themselves on tyrosine residues and phosphorylate their substrates exclusively on S/T residues. They play important roles in cell proliferation, differentiation, survival, and development. The DYRK4 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 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIQTASRRQTFFDSKGFPKNITNNRGKKRYPDSKDLTMVL 80
Cdd:cd14225  228 MWSLGCILAELYTGYPLFPGENEVEQLACIMEVLGLPPPELIENAQRRRLFFDSKGNPRCITNSKGKKRRPNSKDLASAL 307

                         90       100       110
                 ....*....|....*....|....*....|....
gi 537361024  81 KTYDTSFLDFLRRCLVWEPSLRMTPDQALKHAWI 114
Cdd:cd14225  308 KTSDPLFLDFIRRCLEWDPSKRMTPDEALQHEWI 341

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 537361024     1 MWSLGCITAELYTGYPLFPGENEVEQLACIMevlglppagfiqtasrrqtffdskgfpknitnnrGKKRYPDSKDLTMVl 80
Cdd:smart00220 179 IWSLGVILYELLTGKPPFPGDDQLLELFKKI----------------------------------GKPKPPFPPPEWDI- 223

                           90       100       110
                   ....*....|....*....|....*....|....
gi 537361024    81 ktyDTSFLDFLRRCLVWEPSLRMTPDQALKHAWI 114
Cdd:smart00220 224 ---SPEAKDLIRKLLVKDPEKRLTAEEALQHPFF 254

Catalytic domain of the protein kinase, Dual-specificity tYrosine-phosphorylated and -Regulated Kinase 4; 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. DYRK4 is a testis-specific kinase with restricted expression to postmeiotic spermatids. It may function during spermiogenesis, however, it is not required for male fertility. DYRK4 has also been detected in a human teratocarcinoma cell line induced to produce postmitotic neurons. It may have a role in neuronal differentiation. DYRKs autophosphorylate themselves on tyrosine residues and phosphorylate their substrates exclusively on S/T residues. They play important roles in cell proliferation, differentiation, survival, and development. The DYRK4 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 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIQTASRRQTFFDSKGFPKNITNNRGKKRYPDSKDLTMVL 80
Cdd:cd14225  228 MWSLGCILAELYTGYPLFPGENEVEQLACIMEVLGLPPPELIENAQRRRLFFDSKGNPRCITNSKGKKRRPNSKDLASAL 307

                         90       100       110
                 ....*....|....*....|....*....|....
gi 537361024  81 KTYDTSFLDFLRRCLVWEPSLRMTPDQALKHAWI 114
Cdd:cd14225  308 KTSDPLFLDFIRRCLEWDPSKRMTPDEALQHEWI 341

Catalytic domain of the protein kinases, Dual-specificity tYrosine-phosphorylated and -Regulated Kinases 2 and 3; 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 DYRK2 and DYRK3, and similar proteins. Drosophila DYRK2 interacts and phosphorylates the chromatin remodelling factor, SNR1 (Snf5-related 1), and also interacts with the essential chromatin component, trithorax. It may play a role in chromatin remodelling. Vertebrate DYRK2 phosphorylates and regulates the tumor suppressor p53 to induce apoptosis in response to DNA damage. It can also phosphorylate the transcription factor, nuclear factor of activated T cells (NFAT). DYRK2 is overexpressed in lung adenocarcinoma and esophageal carcinomas, and is a predictor for favorable prognosis in lung adenocarcinoma. DYRK3, also called regulatory erythroid kinase (REDK), is highly expressed in erythroid cells and the testis, and is also present in adult kidney and liver. It promotes cell survival by phosphorylating and activating SIRT1, an NAD(+)-dependent protein deacetylase, which promotes p53 deacetylation, resulting in the inhibition of apoptosis. DYRKs autophosphorylate themselves on tyrosine residues and phosphorylate their substrates exclusively on S/T residues. The DYRK2/3 subfamily is part of a larger superfamily that includes the catalytic domains of other S/T kinases, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIQTASRRQTFFDSKGFPKNIT---------------NNR 65
Cdd:cd14224  250 MWSFGCILAELLTGYPLFPGEDEGDQLACMIELLGMPPQKLLETSKRAKNFISSKGYPRYCTvttlpdgsvvlnggrSRR 329

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 537361024  66 GKKR-YPDSKDLTMVLKTYDTS-FLDFLRRCLVWEPSLRMTPDQALKHAWI 114
Cdd:cd14224  330 GKMRgPPGSKDWVTALKGCDDPlFLDFLKRCLEWDPAARMTPSQALRHPWL 380

Catalytic domain of the Dual-specificity protein kinase, YAK1; 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 proteins with similarity to Saccharomyces cerevisiae YAK1 (or Yak1p), a dual-specificity kinase that autophosphorylates at tyrosine residues and phosphorylates substrates on S/T residues. YAK1 phosphorylates and activates the transcription factors Hsf1 and Msn2, which play important roles in cellular homeostasis during stress conditions including heat shock, oxidative stress, and nutrient deficiency. It also phosphorylates the protein POP2, a component of a complex that regulates transcription, under glucose-deprived conditions. It functions as a part of a glucose-sensing system that is involved in controlling growth in yeast. The YAK1 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 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIQTASRRQTFFD--SKGFPKN------------------ 60
Cdd:cd14212  185 MWSLGCIAAELFLGLPLFPGNSEYNQLSRIIEMLGMPPDWMLEKGKNTNKFFKkvAKSGGRStyrlktpeefeaennckl 264

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 537361024  61 ---------------ITNNRGKKRYPDSKDLTMVLKtydTSFLDFLRRCLVWEPSLRMTPDQALKHAWI 114
Cdd:cd14212  265 epgkryfkyktlediIMNYPMKKSKKEQIDKEMETR---LAFIDFLKGLLEYDPKKRWTPDQALNHPFI 330

Catalytic domain of the protein kinase, Dual-specificity tYrosine-phosphorylated and -Regulated Kinase 1; 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. Mammals contain two types of DYRK1 proteins, DYRK1A and DYRK1B. DYRK1A was previously called minibrain kinase homolog (MNBH) or dual-specificity YAK1-related kinase. It phosphorylates various substrates and is involved in many cellular events. It phosphorylates and inhibits the transcription factors, nuclear factor of activated T cells (NFAT) and forkhead in rhabdomyosarcoma (FKHR). It regulates neuronal differentiation by targetting CREB (cAMP response element-binding protein). It also targets many endocytic proteins including dynamin and amphiphysin and may play a role in the endocytic pathway. The gene encoding DYRK1A is located in the DSCR (Down syndrome critical region) of human chromosome 21 and DYRK1A has been implicated in the pathogenesis of DS. DYRK1B, also called minibrain-related kinase (MIRK), is highly expressed in muscle and plays a critical role in muscle differentiation by regulating transcription, cell motility, survival, and cell cycle progression. It is overexpressed in many solid tumors where it acts as a tumor survival factor. DYRKs autophosphorylate themselves on tyrosine residues and phosphorylate their substrates exclusively on S/T residues. The DYRK1 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 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIQTASRRQTFFD---SKGFPKNITNNRGKKRYPDSKDLT 77
Cdd:cd14226  200 MWSLGCILVEMHTGEPLFSGANEVDQMNKIVEVLGMPPVHMLDQAPKARKFFEklpDGTYYLKKTKDGKKYKPPGSRKLH 279

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 537361024  78 MVLKTyDTS-------------------FLDFLRRCLVWEPSLRMTPDQALKH 111
Cdd:cd14226  280 EILGV-ETGgpggrragepghtvedylkFKDLILRMLDYDPKTRITPAEALQH 331

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLAcIME-VLGLPPAGFIQTASRRQTFFDSKG----FPKNITNNRGKKRYPDSKD 75
Cdd:cd14134  214 VWSIGCILVELYTGELLFQTHDNLEHLA-MMErILGPLPKRMIRRAKKGAKYFYFYHgrldWPEGSSSGRSIKRVCKPLK 292

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 537361024  76 LTMVLK-TYDTSFLDFLRRCLVWEPSLRMTPDQALKHAW 113
Cdd:cd14134  293 RLMLLVdPEHRLLFDLIRKMLEYDPSKRITAKEALKHPF 331

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIQTasrrqtfFDSkGFPKNITNNrgkKRYPDSKDLTMVL 80
Cdd:cd07852  196 MWSVGCILGEMLLGKPLFPGTSTLNQLEKIIEVIGRPSAEDIES-------IQS-PFAATMLES---LPPSRPKSLDELF 264

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 537361024  81 KTYDTSFLDFLRRCLVWEPSLRMTPDQALKHAWIHQSRNLKPQP 124
Cdd:cd07852  265 PKASPDALDLLKKLLVFNPNKRLTAEEALRHPYVAQFHNPADEP 308

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAgfiqtasrrqtffdsKGFPKNITNNRGKKRYPDSKDLTMVL 80
Cdd:cd07838  189 MWSVGCIFAELFNRRPLFRGSSEADQLGKIFDVIGLPSE---------------EEWPRNSALPRSSFPSYTPRPFKSFV 253

                         90       100       110
                 ....*....|....*....|....*....|.
gi 537361024  81 KTYDTSFLDFLRRCLVWEPSLRMTPDQALKH 111
Cdd:cd07838  254 PEIDEEGLDLLKKMLTFNPHKRISAFEALQH 284

Catalytic domain of CMGC family Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The CMGC family consists of Cyclin-Dependent protein Kinases (CDKs), Mitogen-activated protein kinases (MAPKs) such as Extracellular signal-regulated kinase (ERKs), c-Jun N-terminal kinases (JNKs), and p38, and other kinases. CDKs belong to a large subfamily of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. MAPKs serve as important mediators of cellular responses to extracellular signals. They control critical cellular functions including differentiation, proliferation, migration, and apoptosis. They are also implicated in the pathogenesis of many diseases including multiple types of cancer, stroke, diabetes, and chronic inflammation. Other members of the CMGC family include casein kinase 2 (CK2), Dual-specificity tYrosine-phosphorylated and -Regulated Kinase (DYRK), Glycogen Synthase Kinase 3 (GSK3), among many others. The CMGC 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 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPagfiqtasrrqtffdskgfpknitnnrgkkrypdskdltmvl 80
Cdd:cd05118  184 IWSLGCILAELLTGRPLFPGDSEVDQLAKIVRLLGTPE------------------------------------------ 221

                         90       100       110
                 ....*....|....*....|....*....|....
gi 537361024  81 ktydtsFLDFLRRCLVWEPSLRMTPDQALKHAWI 114
Cdd:cd05118  222 ------ALDLLSKMLKYDPAKRITASQALAHPYF 249

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPpagfiqtasRRQTFFDSKGFPKnitNNRGKKRYPdSKDLTMVL 80
Cdd:cd07836  184 IWSVGCIMAEMITGRPLFPGTNNEDQLLKIFRIMGTP---------TESTWPGISQLPE---YKPTFPRYP-PQDLQQLF 250

                         90       100       110
                 ....*....|....*....|....*....|...
gi 537361024  81 KTYDTSFLDFLRRCLVWEPSLRMTPDQALKHAW 113
Cdd:cd07836  251 PHADPLGIDLLHRLLQLNPELRISAHDALQHPW 283

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLG-LPPagfiqtasRRQTFFDSKgfpkniTNNRGkKRYPDSKDLTMV 79
Cdd:cd07833  185 VWAIGCIMAELLDGEPLFPGDSDIDQLYLIQKCLGpLPP--------SHQELFSSN------PRFAG-VAFPEPSQPESL 249

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 537361024  80 LKTYDTSF----LDFLRRCLVWEPSLRMTPDQALKHAW 113
Cdd:cd07833  250 ERRYPGKVsspaLDFLKACLRMDPKERLTCDELLQHPY 287

Catalytic domain of the Serine/Threonine Kinase, p38gamma Mitogen-Activated Protein Kinase (also called MAPK12); STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. p38gamma/MAPK12 is predominantly expressed in skeletal muscle. Unlike p38alpha and p38beta, p38gamma is insensitive to pyridinylimidazoles. It displays an antagonizing function compared to p38alpha. p38gamma inhibits, while p38alpha stimulates, c-Jun phosphorylation and AP-1 mediated transcription. p38gamma also plays a role in the signaling between Ras and the estrogen receptor and has been implicated to increase cell invasion and breast cancer progression. In Xenopus, p38gamma is critical in the meiotic maturation of oocytes. p38 kinases are MAPKs, serving as important mediators of cellular responses to extracellular signals. They are activated by the MAPK kinases MKK3 and MKK6, which in turn are activated by upstream MAPK kinase kinases including TAK1, ASK1, and MLK3, in response to cellular stresses or inflammatory cytokines. The p38gamma 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 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIQtasRRQTfFDSKGFPKNITNNRgkkrypdSKDLTMVL 80
Cdd:cd07880  199 IWSVGCIMAEMLTGKPLFKGHDHLDQLMEIMKVTGTPSKEFVQ---KLQS-EDAKNYVKKLPRFR-------KKDFRSLL 267

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 537361024  81 KTYDTSFLDFLRRCLVWEPSLRMTPDQALKHAWIHQSRNLKPQPRPQ 127
Cdd:cd07880  268 PNANPLAVNVLEKMLVLDAESRITAAEALAHPYFEEFHDPEDETEAP 314

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIQTASRRQTFFDSkgFPKnitnnrgkkrYPdSKDLTMVL 80
Cdd:cd07835  183 IWSVGCIFAEMVTRRPLFPGDSEIDQLFRIFRTLGTPDEDVWPGVTSLPDYKPT--FPK----------WA-RQDLSKVV 249

                         90       100       110
                 ....*....|....*....|....*....|...
gi 537361024  81 KTYDTSFLDFLRRCLVWEPSLRMTPDQALKHAW 113
Cdd:cd07835  250 PSLDEDGLDLLSQMLVYDPAKRISAKAALQHPY 282

Catalytic domain of the Serine/Threonine Kinase, Pre-mRNA-Processing factor 4; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PRP4 phosphorylates a number of factors involved in the formation of active spliceosomes, which catalyze pre-mRNA splicing. It phosphorylates PRP6 and PRP31, components of the U4/U6-U5 tri-small nuclear ribonucleoprotein (snRNP), during spliceosomal complex formation. In fission yeast, PRP4 phosphorylates the splicing factor PRP1 (U5-102 kD in mammals). Thus, PRP4 plays a key role in regulating spliceosome assembly and pre-mRNA splicing. It also plays an important role in mitosis by acting as a spindle assembly checkpoint kinase that is required for chromosome alignment and the recruitment of the checkpoint proteins MPS1, MAD1, and MAD2 at kinetochores. The PRP4 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 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIQTASRRQTFFDSKGFPKNI----TNNRGKKRYPD---- 72
Cdd:cd14135  187 MWSVGCTLYELYTGKILFPGKTNNHMLKLMMDLKGKFPKKMLRKGQFKDQHFDENLNFIYRevdkVTKKEVRRVMSdikp 266

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 537361024  73 SKDLTMVLKTYDTS----------FLDFLRRCLVWEPSLRMTPDQALKHAWI 114
Cdd:cd14135  267 TKDLKTLLIGKQRLpdedrkkllqLKDLLDKCLMLDPEKRITPNEALQHPFI 318

Catalytic domain of the Serine/Threonine Kinase, Extracellular signal-Regulated Kinase 5; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. ERK5 (also called Big MAPK1 (BMK1) or MAPK7) has a unique C-terminal extension, making it approximately twice as big as other MAPKs. This extension contains transcriptional activation capability which is inhibited by the N-terminal half. ERK5 is activated in response to growth factors and stress by a cascade that leads to its phosphorylation by the MAP2K MEK5, which in turn is regulated by the MAP3Ks MEKK2 and MEKK3. Activated ERK5 phosphorylates its targets including myocyte enhancer factor 2 (MEF2), Sap1a, c-Myc, and RSK. It plays a role in EGF-induced cell proliferation during the G1/S phase transition. Studies on knockout mice revealed that ERK5 is essential for cardiovascular development and plays an important role in angiogenesis. It is also critical for neural differentiation and survival. The ERK5 pathway has been implicated in the pathogenesis of many diseases including cancer, cardiac hypertrophy, and atherosclerosis. MAPKs are important mediators of cellular responses to extracellular signals. The ERK5 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 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIQT--ASRRQTFFDSkgFPkNITNNRGKKRYPDskdltm 78
Cdd:cd07855  197 MWSVGCIFAEMLGRRQLFPGKNYVHQLQLILTVLGTPSQAVINAigADRVRRYIQN--LP-NKQPVPWETLYPK------ 267

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 537361024  79 vlKTYDTsfLDFLRRCLVWEPSLRMTPDQALKHAWIHQ 116
Cdd:cd07855  268 --ADQQA--LDLLSQMLRFDPSERITVAEALQHPFLAK 301

Catalytic domain of the Serine/Threonine Kinase, Cell Division Cycle 2-like 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CDC2L1, also called PITSLRE, exists in different isoforms which are named using the alias CDK11(p). The CDC2L1 gene produces two protein products, CDK11(p110) and CDK11(p58). CDC2L1 is also represented by the caspase-processed CDK11(p46). CDK11(p110), the major isoform, associates with cyclin L and is expressed throughout the cell cycle. It is involved in RNA processing and the regulation of transcription. CDK11(p58) associates with cyclin D3 and is expressed during the G2/M phase of the cell cycle. It plays roles in spindle morphogenesis, centrosome maturation, sister chromatid cohesion, and the completion of mitosis. CDK11(p46) is formed from the larger isoforms by caspases during TNFalpha- and Fas-induced apoptosis. It functions as a downstream effector kinase in apoptotic signaling pathways and interacts with eukaryotic initiation factor 3f (eIF3f), p21-activated kinase (PAK1), and Ran-binding protein (RanBPM). CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. The CDC2L1 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 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLP-----PaGFIQTASRRQTFFdskgfpKNITNNRGKKRYPdSKD 75
Cdd:cd07843  190 MWSVGCIFAELLTKKPLFPGKSEIDQLNKIFKLLGTPtekiwP-GFSELPGAKKKTF------TKYPYNQLRKKFP-ALS 261

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 537361024  76 LTmvlktyDTSFlDFLRRCLVWEPSLRMTPDQALKHAWI 114
Cdd:cd07843  262 LS------DNGF-DLLNRLLTYDPAKRISAEDALKHPYF 293

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIQTASRRQTffdskgfPKNITNNRGKKRYPDSKDLTMVl 80
Cdd:cd07859  191 IWSIGCIFAEVLTGKPLFPGKNVVHQLDLITDLLGTPSPETISRVRNEKA-------RRYLSSMRKKQPVPFSQKFPNA- 262

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 537361024  81 ktyDTSFLDFLRRCLVWEPSLRMTPDQALKHAWIHQSRNLKPQPRPQTLRKSNsfFPSETRK 142
Cdd:cd07859  263 ---DPLALRLLERLLAFDPKDRPTAEEALADPYFKGLAKVEREPSAQPITKLE--FEFERRR 319

Catalytic domain of the Serine/Threonine Kinase, Serine-aRginine Protein Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. SRPKs phosphorylate and regulate splicing factors from the SR protein family by specifically phosphorylating multiple serine residues residing in SR/RS dipeptide motifs (also known as RS domains). Phosphorylation of the RS domains enhances interaction with transportin SR and facilitates entry of the SR proteins into the nucleus. SRPKs contain a nonconserved insert domain, within the well-conserved catalytic kinase domain, that regulates their subcellular localization. They play important roles in mediating pre-mRNA processing and mRNA maturation, as well as other cellular functions such as chromatin reorganization, cell cycle and p53 regulation, and metabolic signaling. Vertebrates contain three distinct SRPKs, called SRPK1-3. The SRPK homolog in budding yeast, Sky1p, recognizes and phosphorylates its substrate Npl3p, which lacks a classic RS domain but contains a single RS dipeptide at the C-terminus of its RGG domain. Npl3p is a shuttling heterogeneous nuclear ribonucleoprotein (hnRNP) that exports a distinct class of mRNA from the nucleus to the cytoplasm. The SRPK 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 537361024   1 MWSLGCITAELYTGYPLF---PGEN---EVEQLACIMEVLGLPPAGFIQTASRRQTFFDSKGFPKNITNnrgKKRYPdsk 74
Cdd:cd14136  201 IWSTACMAFELATGDYLFdphSGEDysrDEDHLALIIELLGRIPRSIILSGKYSREFFNRKGELRHISK---LKPWP--- 274

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 537361024  75 dLTMVLK-TYDTS------FLDFLRRCLVWEPSLRMTPDQALKHAWI 114
Cdd:cd14136  275 -LEDVLVeKYKWSkeeakeFASFLLPMLEYDPEKRATAAQCLQHPWL 320

Catalytic domain of the Serine/Threonine Kinases, Plant TEY Mitogen-Activated Protein Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Plant MAPKs are typed based on the conserved phosphorylation motif present in the activation loop, TEY and TDY. This subfamily represents the TEY subtype of plant MAPKs and is further subdivided into three groups (A, B, and C). Group A is represented by AtMPK3, AtMPK6, Nicotiana tabacum BTF4 (NtNTF4), among others. They are mostly involved in environmental and hormonal responses. AtMPK3 and AtMPK6 are also key regulators for stomatal development and patterning. Group B is represented by AtMPK4, AtMPK13, and NtNTF6, among others. They may be involved in both cell division and environmental stress response. AtMPK4 also participates in regulating innate immunity. Group C is represented by AtMPK1, AtMPK2, NtNTF3, Oryza sativa MAPK4 (OsMAPK4), among others. They may also be involved in stress responses. AtMPK1 and AtMPK2 are activated following mechanical injury and in the presence of stress chemicals such as jasmonic acid, hydrogen peroxide and abscisic acid. OsMAPK4 is also called OsMSRMK3 for Multiple Stress-Responsive MAPK3. In plants, MAPKs are associated with physiological, developmental, hormonal, and stress responses. Some plants show numerous gene duplications of MAPKs; Arabidopsis thaliana harbors at least 20 MAPKs, named AtMPK1-20. The TEY MAPK 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 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPA---GFIQTASRRQtffdskgFPKNITNNRG---KKRYPDSK 74
Cdd:cd07858  192 VWSVGCIFAELLGRKPLFPGKDYVHQLKLITELLGSPSEedlGFIRNEKARR-------YIRSLPYTPRqsfARLFPHAN 264

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 537361024  75 DLTmvlktydtsfLDFLRRCLVWEPSLRMTPDQALKHAWI 114
Cdd:cd07858  265 PLA----------IDLLEKMLVFDPSKRITVEEALAHPYL 294

Catalytic domain of the Serine/Threonine Kinase, Fungal Mitogen-Activated Protein Kinase MPK1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of the MAPKs MPK1 from Saccharomyces cerevisiae, Pmk1 from Schizosaccharomyces pombe, and similar proteins. MPK1 (also called Slt2) and Pmk1 (also called Spm1) are stress-activated MAPKs that regulate the cell wall integrity pathway, and are therefore important in the maintainance of cell shape, cell wall construction, morphogenesis, and ion homeostasis. MPK1 is activated in response to cell wall stress including heat stimulation, osmotic shock, UV irradiation, and any agents that interfere with cell wall biogenesis such as chitin antagonists, caffeine, or zymolase. MPK1 is regulated by the MAP2Ks Mkk1/2, which are regulated by the MAP3K Bck1. Pmk1 is also activated by multiple stresses including elevated temperatures, hyper- or hypotonic stress, glucose deprivation, exposure to cell-wall damaging compounds, and oxidative stress. It is regulated by the MAP2K Pek1, which is regulated by the MAP3K Mkh1. MAPKs are important mediators of cellular responses to extracellular signals. The MPK1 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 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIQ--TASRRQTFFDSKGFP--KNITNNrgkkrYPDSKDL 76
Cdd:cd07857  193 VWSVGCILAELLGRKPVFKGKDYVDQLNQILQVLGTPDEETLSriGSPKAQNYIRSLPNIpkKPFESI-----FPNANPL 267

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 537361024  77 TmvlktydtsfLDFLRRCLVWEPSLRMTPDQALKHAWI 114
Cdd:cd07857  268 A----------LDLLEKLLAFDPTKRISVEEALEHPYL 295

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIQT--ASRRQTFFDSKGFPKNITNNrgkKRYPDSkdltm 78
Cdd:cd07849  193 IWSVGCILAEMLSNRPLFPGKDYLHQLNLILGILGTPSQEDLNCiiSLKARNYIKSLPFKPKVPWN---KLFPNA----- 264

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 537361024  79 vlktyDTSFLDFLRRCLVWEPSLRMTPDQALKHAWIHQ 116
Cdd:cd07849  265 -----DPKALDLLDKMLTFNPHKRITVEEALAHPYLEQ 297

Catalytic domain of the Serine/Threonine Kinases, Cyclin-Dependent protein Kinase Like 1 and 4; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CDKL1, also called p42 KKIALRE, is a glial protein that is upregulated in gliosis. It is present in neuroblastoma and A431 human carcinoma cells, and may be implicated in neoplastic transformation. The function of CDKL4 is unknown. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. The CDKL1/4 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 537361024   2 WSLGCITAELYTGYPLFPGENEVEQLACIMEVLG-LPPagfiqtasRRQTFFDSKGFPKNITNNRGKKRYPdskdLTMVL 80
Cdd:cd07847  185 WAIGCVFAELLTGQPLWPGKSDVDQLYLIRKTLGdLIP--------RHQQIFSTNQFFKGLSIPEPETREP----LESKF 252

                         90       100       110
                 ....*....|....*....|....*....|...
gi 537361024  81 KTYDTSFLDFLRRCLVWEPSLRMTPDQALKHAW 113
Cdd:cd07847  253 PNISSPALSFLKGCLQMDPTERLSCEELLEHPY 285

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIQTASRRQtffdSKGFPKNITnnrgkkrYPDSKDLTMVL 80
Cdd:cd07877  201 IWSVGCIMAELLTGRTLFPGTDHIDQLKLILRLVGTPGAELLKKISSES----ARNYIQSLT-------QMPKMNFANVF 269

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 537361024  81 KTYDTSFLDFLRRCLVWEPSLRMTPDQALKHAWIHQSRNLKPQPRPQTLRKS 132
Cdd:cd07877  270 IGANPLAVDLLEKMLVLDSDKRITAAQALAHAYFAQYHDPDDEPVADPYDQS 321

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPPAGFIqtaSRRQTFFdskgfpKNITNNRGK-------KRYPDS 73
Cdd:cd07850  184 IWSVGCIMGEMIRGTVLFPGTDHIDQWNKIIEQLGTPSDEFM---SRLQPTV------RNYVENRPKyagysfeELFPDV 254

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 537361024  74 ---KDLTMVLKTYDTSFLDFLRRCLVWEPSLRMTPDQALKHAWIHQ 116
Cdd:cd07850  255 lfpPDSEEHNKLKASQARDLLSKMLVIDPEKRISVDDALQHPYINV 300

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 537361024   1 MWSLGCITAELYTGYPLFPGENEVEQLACIMEVLGLPpagfiqTASRRQTFFDSKGFPknitNNRGKKRYPDSkdLTMVL 80
Cdd:cd07866  210 IWGIGCVFAEMFTRRPILQGKSDIDQLHLIFKLCGTP------TEETWPGWRSLPGCE----GVHSFTNYPRT--LEERF 277

                         90       100       110
                 ....*....|....*....|....*....|...
gi 537361024  81 KTYDTSFLDFLRRCLVWEPSLRMTPDQALKHAW 113
Cdd:cd07866  278 GKLGPEGLDLLSKLLSLDPYKRLTASDALEHPY 310