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 645930265   1 AIYQGATVAVKQVKKCSKNSlASRQSFWAELNVAHLDHNNVVRVVAASTCspASQDSVGTIIMEYVGISTLHHIIYGTdc 80
Cdd:cd13979   22 ATYKGETVAVKIVRRRRKNR-ASRQSFWAELNAARLRHENIVRVLAAETG--TDFASLGLIIMEYCGNGTLQQLIYEG-- 96

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 645930265  81 kiakwkdvglggvHVPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:cd13979   97 -------------SEPLPLAHRILISLDIARALRFCHSHGIVHLDVKPANILIS 137

Catalytic domain of the Serine/Threonine kinase, Oocyte maturation factor Mos; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Mos (or c-Mos) is a germ-cell specific kinase that plays roles in both the release of primary arrest and the induction of secondary arrest in oocytes. It is expressed towards the end of meiosis I and is quickly degraded upon fertilization. It is a component of the cytostatic factor (CSF), which is responsible for metaphase II arrest. In addition, Mos activates a phoshorylation cascade that leads to the activation of the p34 subunit of MPF (mitosis-promoting factor or maturation promoting factor), a cyclin-dependent kinase that is responsible for the release of primary arrest in meiosis I. The Mos 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 645930265   1 AIYQGATVAVKQVKKCSKNSlASRQSFWAELNVAHLDHNNVVRVVAASTCspASQDSVGTIIMEYVGISTLHHIIYGTdc 80
Cdd:cd13979   22 ATYKGETVAVKIVRRRRKNR-ASRQSFWAELNAARLRHENIVRVLAAETG--TDFASLGLIIMEYCGNGTLQQLIYEG-- 96

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 645930265  81 kiakwkdvglggvHVPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:cd13979   97 -------------SEPLPLAHRILISLDIARALRFCHSHGIVHLDVKPANILIS 137

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 645930265     5 GATVAVKQVKKcsKNSLASRQSFWAELNV-AHLDHNNVVRVVAASTcspaSQDSVgTIIMEYVGISTLHHIIYGtdckia 83
Cdd:smart00220  24 GKLVAIKVIKK--KKIKKDRERILREIKIlKKLKHPNIVRLYDVFE----DEDKL-YLVMEYCEGGDLFDLLKK------ 90

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|.
gi 645930265    84 kwkdvglggvHVPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:smart00220  91 ----------RGRLSEDEARFYLRQILSALEYLHSKGIVHRDLKPENILLD 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        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 645930265    7 TVAVKQVKKCSKNSlaSRQSFWAELNV-AHLDHNNVVRVVAASTCSPASQdsvgtIIMEYVGISTLHHiiYGTDCKIakw 85
Cdd:pfam07714  30 KVAVKTLKEGADEE--EREDFLEEASImKKLDHPNIVKLLGVCTQGEPLY-----IVTEYMPGGDLLD--FLRKHKR--- 97

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 645930265   86 kdvglggvhvPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:pfam07714  98 ----------KLTLKDLLSMALQIAKGMEYLESKNFVHRDLAARNCLVS 136

Catalytic domain of the Serine/Threonine kinase, Oocyte maturation factor Mos; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Mos (or c-Mos) is a germ-cell specific kinase that plays roles in both the release of primary arrest and the induction of secondary arrest in oocytes. It is expressed towards the end of meiosis I and is quickly degraded upon fertilization. It is a component of the cytostatic factor (CSF), which is responsible for metaphase II arrest. In addition, Mos activates a phoshorylation cascade that leads to the activation of the p34 subunit of MPF (mitosis-promoting factor or maturation promoting factor), a cyclin-dependent kinase that is responsible for the release of primary arrest in meiosis I. The Mos 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 645930265   1 AIYQGATVAVKQVKKCSKNSlASRQSFWAELNVAHLDHNNVVRVVAASTCspASQDSVGTIIMEYVGISTLHHIIYGTdc 80
Cdd:cd13979   22 ATYKGETVAVKIVRRRRKNR-ASRQSFWAELNAARLRHENIVRVLAAETG--TDFASLGLIIMEYCGNGTLQQLIYEG-- 96

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 645930265  81 kiakwkdvglggvHVPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:cd13979   97 -------------SEPLPLAHRILISLDIARALRFCHSHGIVHLDVKPANILIS 137

Serine/threonine protein kinase [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 645930265   5 GATVAVKQVKKCSKNSLASRQSFWAELNV-AHLDHNNVVRVVAASTcspasQDSVGTIIMEYV-GIsTLHHIIygtdcki 82
Cdd:COG0515   32 GRPVALKVLRPELAADPEARERFRREARAlARLNHPNIVRVYDVGE-----EDGRPYLVMEYVeGE-SLADLL------- 98

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 645930265  83 akwKDVGlggvhvPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:COG0515   99 ---RRRG------PLPPAEALRILAQLAEALAAAHAAGIVHRDIKPANILLT 141

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 645930265   1 AIYQGATVAVKQVKKCSKNSLASRQsFWAELNV-AHLDHNNVVRVVAASTcspasQDSVGTIIMEYVGISTLHHIIYGTD 79
Cdd:cd13999   12 GKWRGTDVAIKKLKVEDDNDELLKE-FRREVSIlSKLRHPNIVQFIGACL-----SPPPLCIVTEYMPGGSLYDLLHKKK 85

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 645930265  80 ckiakwkdvglggvhVPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:cd13999   86 ---------------IPLSWSLRLKIALDIARGMNYLHSPPIIHRDLKSLNILLD 125

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 645930265   5 GATVAVKQVKkCSKNSLASRQSFWAELNV-AHLDHNNVVRVVAASTcspaSQDSVgTIIMEYVGISTLHHIIygtdckia 83
Cdd:cd06606   25 GELMAVKEVE-LSGDSEEELEALEREIRIlSSLKHPNIVRYLGTER----TENTL-NIFLEYVPGGSLASLL-------- 90

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 645930265  84 kwKDVGlggvhvPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:cd06606   91 --KKFG------KLPEPVVRKYTRQILEGLEYLHSNGIVHRDIKGANILVD 133

Catalytic domain of Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. They can be classified into receptor and non-receptor tyr kinases. PTKs play important roles in many cellular processes including, lymphocyte activation, epithelium growth and maintenance, metabolism control, organogenesis regulation, survival, proliferation, differentiation, migration, adhesion, motility, and morphogenesis. Receptor tyr kinases (RTKs) are integral membrane proteins which contain an extracellular ligand-binding region, a transmembrane segment, and an intracellular tyr kinase domain. RTKs are usually activated through ligand binding, which causes dimerization and autophosphorylation of the intracellular tyr kinase catalytic domain, leading to intracellular signaling. Some RTKs are orphan receptors with no known ligands. Non-receptor (or cytoplasmic) tyr kinases are distributed in different intracellular compartments and are usually multi-domain proteins containing a catalytic tyr kinase domain as well as various regulatory domains such as SH3 and SH2. PTKs are usually autoinhibited and require a mechanism for activation. In many PTKs, the phosphorylation of tyr residues in the activation loop is essential for optimal activity. Aberrant expression of PTKs is associated with many development abnormalities and cancers.The PTK family is part of a larger superfamily that includes the catalytic domains of serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 645930265   7 TVAVKQVKKCSknSLASRQSFWAELNV-AHLDHNNVVRVVAASTcspaSQDSVgTIIMEYVGISTLHHiiygtdcKIAKW 85
Cdd:cd00192   25 DVAVKTLKEDA--SESERKDFLKEARVmKKLGHPNVVRLLGVCT----EEEPL-YLVMEYMEGGDLLD-------FLRKS 90

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 645930265  86 KDVGLGGVHVPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:cd00192   91 RPVFPSPEPSTLSLKDLLSFAIQIAKGMEYLASKKFVHRDLAARNCLVG 139

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 645930265     7 TVAVKQVKKCSknSLASRQSFWAELNV-AHLDHNNVVRVVAASTcspasQDSVGTIIMEYV-GISTLHHIiygtdcKIAK 84
Cdd:smart00221  30 EVAVKTLKEDA--SEQQIEEFLREARImRKLDHPNIVKLLGVCT-----EEEPLMIVMEYMpGGDLLDYL------RKNR 96

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|
gi 645930265    85 wkdvglggvHVPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:smart00221  97 ---------PKELSLSDLLSFALQIARGMEYLESKNFIHRDLAARNCLVG 137

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 645930265     7 TVAVKQVKKCSKNSLasRQSFWAELNV-AHLDHNNVVRVVAAstcspASQDSVGTIIMEYV-GISTLHHiiygtdckiak 84
Cdd:smart00219  30 EVAVKTLKEDASEQQ--IEEFLREARImRKLDHPNVVKLLGV-----CTEEEPLYIVMEYMeGGDLLSY----------- 91

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|
gi 645930265    85 wkdvgLGGVHVPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:smart00219  92 -----LRKNRPKLSLSDLLSFALQIARGMEYLESKNFIHRDLAARNCLVG 136

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 645930265    7 TVAVKQVKKCSKNSlaSRQSFWAELNV-AHLDHNNVVRVVAASTCSPASQdsvgtIIMEYVGISTLHHiiYGTDCKIakw 85
Cdd:pfam07714  30 KVAVKTLKEGADEE--EREDFLEEASImKKLDHPNIVKLLGVCTQGEPLY-----IVTEYMPGGDLLD--FLRKHKR--- 97

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 645930265   86 kdvglggvhvPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:pfam07714  98 ----------KLTLKDLLSMALQIAKGMEYLESKNFVHRDLAARNCLVS 136

Catalytic domain of the Serine/Threonine Kinase, Never In Mitosis gene A (NIMA)-related kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The Nek family is composed of 11 different mammalian members (Nek1-11) with similarity to the catalytic domain of Aspergillus nidulans NIMA kinase, the founding member of the Nek family, which was identified in a screen for cell cycle mutants that were prevented from entering mitosis. Neks contain a conserved N-terminal catalytic domain and a more divergent C-terminal regulatory region of various sizes and structures. They are involved in the regulation of downstream processes following the activation of Cdc2, and many of their functions are cell cycle-related. They play critical roles in microtubule dynamics during ciliogenesis and mitosis. The Nek 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 645930265   5 GATVAVKQVKkCSKNSLASRQSFWAELNV-AHLDHNNVVRVVAastcspaSQDSVGT--IIMEYVGISTLHHiiygtdcK 81
Cdd:cd08215   25 GKLYVLKEID-LSNMSEKEREEALNEVKLlSKLKHPNIVKYYE-------SFEENGKlcIVMEYADGGDLAQ-------K 89

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 645930265  82 IAKWKDVGlggvhVPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:cd08215   90 IKKQKKKG-----QPFPEEQILDWFVQICLALKYLHSRKILHRDLKTQNIFLT 137

Catalytic domain of the Serine/Threonine kinase, eukaryotic translation Initiation Factor 2-Alpha Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. EIF2AKs phosphorylate the alpha subunit of eIF-2, resulting in the downregulation of protein synthesis. eIF-2 phosphorylation is induced in response to cellular stresses including virus infection, heat shock, nutrient deficiency, and the accummulation of unfolded proteins, among others. There are four distinct kinases that phosphorylate eIF-2 and control protein synthesis under different stress conditions: General Control Non-derepressible-2 (GCN2) which is activated during amino acid or serum starvation; protein kinase regulated by RNA (PKR) which is activated by double stranded RNA; heme-regulated inhibitor kinase (HRI) which is activated under heme-deficient conditions; and PKR-like endoplasmic reticulum kinase (PERK) which is activated when misfolded proteins accumulate in the ER. The EIF2AK 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 645930265   5 GATVAVKQVKKCSKNSLASRQSFWAELNvAHLDHNNVVRVVAAstcspASQDSVGTIIMEYVGISTLHHIIygtdckiak 84
Cdd:cd13996   31 GVTYAIKKIRLTEKSSASEKVLREVKAL-AKLNHPNIVRYYTA-----WVEEPPLYIQMELCEGGTLRDWI--------- 95

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 645930265  85 wkdvGLGGVHVPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:cd13996   96 ----DRRNSSSKNDRKLALELFKQILKGVSYIHSKGIVHRDLKPSNIFLD 141

Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MEKK1 is a MAPK kinase kinase (MAPKKK or MKKK) that phosphorylates and activates activates the ERK1/2 and c-Jun N-terminal kinase (JNK) pathways by activating their respective MAPKKs, MEK1/2 and MKK4/MKK7, respectively. MEKK1 is important in regulating cell survival and apoptosis. MEKK1 also plays a role in cell migration, tissue maintenance and homeostasis, and wound healing. The MEKK1 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 645930265   5 GATVAVKQVKKCsKNSLASR----QSFWAELNV-AHLDHNNVVRVVAAsTCspasQDSVGTIIMEYV---GISTLHHIiY 76
Cdd:cd06630   25 GTLMAVKQVSFC-RNSSSEQeevvEAIREEIRMmARLNHPNIVRMLGA-TQ----HKSHFNIFVEWMaggSVASLLSK-Y 97

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 645930265  77 GtdckiakwkdvglggvhvPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFI 133
Cdd:cd06630   98 G------------------AFSENVIINYTLQILRGLAYLHDNQIIHRDLKGANLLV 136

Catalytic domain of Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 3-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of MEKK3, MEKK2, and related proteins; all contain an N-terminal PB1 domain, which mediates oligomerization, and a C-terminal catalytic domain. MEKK2 and MEKK3 are MAPK kinase kinases (MAPKKKs or MKKK) that activate MEK5 (also called MKK5), which activates ERK5. The ERK5 cascade plays roles in promoting cell proliferation, differentiation, neuronal survival, and neuroprotection. MEKK3 plays an essential role in embryonic angiogenesis and early heart development. MEKK2 and MEKK3 can also activate the MAPKs, c-Jun N-terminal kinase (JNK) and p38, through their respective MAPKKs. The MEKK3-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 645930265   5 GATVAVKQVKKCSKNSLASR--QSFWAELNV-AHLDHNnvvRVVAASTCspASQDSVGTIIMEYV-GISTLHHI-IYGtd 79
Cdd:cd06625   25 GRELAVKQVEIDPINTEASKevKALECEIQLlKNLQHE---RIVQYYGC--LQDEKSLSIFMEYMpGGSVKDEIkAYG-- 97

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 645930265  80 ckiakwkdvglggvhvPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANI 131
Cdd:cd06625   98 ----------------ALTENVTRKYTRQILEGLAYLHSNMIVHRDIKGANI 133

Catalytic domain, repeat 2, of the Serine/Threonine kinase, eukaryotic translation Initiation Factor 2-Alpha Kinase 4 or General Control Non-derepressible-2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. GCN2 (or EIF2AK4) is activated by amino acid or serum starvation and UV irradiation. It induces GCN4, a transcriptional activator of amino acid biosynthetic genes, leading to increased production of amino acids under amino acid-deficient conditions. In serum-starved cells, GCN2 activation induces translation of the stress-responsive transcription factor ATF4, while under UV stress, GCN2 triggers transcriptional rescue via NF-kB signaling. GCN2 contains an N-terminal RWD, a degenerate kinase-like (repeat 1), the catalytic kinase (repeat 2), a histidyl-tRNA synthetase (HisRS)-like, and a C-terminal ribosome-binding and dimerization (RB/DD) domains. Its kinase domain is activated via conformational changes as a result of the binding of uncharged tRNA to the HisRS-like domain. EIF2AKs phosphorylate the alpha subunit of eIF-2, resulting in the overall downregulation of protein synthesis. The GCN2 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 645930265   9 AVKQVKKCSKNSLASRqsFWAELN-VAHLDHNNVVRVVAASTcspasQDSVGTIIMEYVGISTLHHIIygtDCKIAKWKD 87
Cdd:cd14046   35 AIKKIKLRSESKNNSR--ILREVMlLSRLNHQHVVRYYQAWI-----ERANLYIQMEYCEKSTLRDLI---DSGLFQDTD 104

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 645930265  88 vglggvhvplsitEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFI 133
Cdd:cd14046  105 -------------RLWRLFRQILEGLAYIHSQGIIHRDLKPVNIFL 137

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 645930265  35 HLDHNNVVRVVAASTCSPASQDSVGTIIMEYVgistlhhiiygtDCKIAKWKDvglggvHVP---LSITEALRYSCDIAA 111
Cdd:cd07838   57 SFEHPNVVRLLDVCHGPRTDRELKLTLVFEHV------------DQDLATYLD------KCPkpgLPPETIKDLMRQLLR 118

                         90       100
                 ....*....|....*....|...
gi 645930265 112 GLVFLHSHLIVHLDLKPANIFIT 134
Cdd:cd07838  119 GLDFLHSHRIVHRDLKPQNILVT 141

Catalytic domain of C-terminal Src kinase-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. This subfamily is composed of Csk, Chk, and similar proteins. They are cytoplasmic (or nonreceptor) PTKs containing the Src homology domains, SH3 and SH2, N-terminal to the catalytic tyr kinase domain. They negatively regulate the activity of Src kinases that are anchored to the plasma membrane. To inhibit Src kinases, Csk and Chk are translocated to the membrane via binding to specific transmembrane proteins, G-proteins, or adaptor proteins near the membrane. Csk catalyzes the tyr phosphorylation of the regulatory C-terminal tail of Src kinases, resulting in their inactivation. Chk inhibit Src kinases using a noncatalytic mechanism by simply binding to them. As negative regulators of Src kinases, Csk and Chk play important roles in cell proliferation, survival, and differentiation, and consequently, in cancer development and progression. The Csk-like 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 645930265   1 AIYQGATVAVKQVkkcsKNSLASRQSFWAELNV-AHLDHNNVVRVVAASTcspasQDSVGTIIMEYVGISTLhhIIYgtd 79
Cdd:cd05039   25 GDYRGQKVAVKCL----KDDSTAAQAFLAEASVmTTLRHPNLVQLLGVVL-----EGNGLYIVTEYMAKGSL--VDY--- 90

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 645930265  80 ckiakwkdVGLGGVHVpLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFI 133
Cdd:cd05039   91 --------LRSRGRAV-ITRKDQLGFALDVCEGMEYLESKKFVHRDLAARNVLV 135

Catalytic domain of the Serine/Threonine Kinase, Cell Cycle-Related Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CCRK was previously called p42. It is a Cyclin-Dependent Kinase (CDK)-Activating Kinase (CAK) which is essential for the activation of CDK2. It is indispensable for cell growth and has been implicated in the progression of glioblastoma multiforme. In the heart, a splice variant of CCRK with a different C-terminal half is expressed; this variant promotes cardiac cell growth and survival and is significantly down-regulated during the development of heart failure. The CCRK 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 645930265   5 GATVAVKQV-----KKCSKNSLASRQSFWAELNvahlDHNNVVRVVAASTcspasqdsVGT---IIMEYVGiSTLHHIIY 76
Cdd:cd07832   25 GETVALKKValrklEGGIPNQALREIKALQACQ----GHPYVVKLRDVFP--------HGTgfvLVFEYML-SSLSEVLR 91

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 645930265  77 GTDckiakwkdvglggvhVPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFI 133
Cdd:cd07832   92 DEE---------------RPLTEAQVKRYMRMLLKGVAYMHANRIMHRDLKPANLLI 133

Catalytic domain of the Protein Tyrosine Kinases, Fungal Wee1 proteins; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. This subfamily is composed of fungal Wee1 proteins, also called Swe1 in budding yeast and Mik1 in fission yeast. Yeast Wee1 is required to control cell size. Wee1 is a cell cycle checkpoint kinase that helps keep the cyclin-dependent kinase CDK1 in an inactive state through phosphorylation of an N-terminal tyr (Y15) residue. During the late G2 phase, CDK1 is activated and mitotic entry is promoted by the removal of this inhibitory phosphorylation by the phosphatase Cdc25. Although Wee1 is functionally a tyr kinase, it is more closely related to serine/threonine kinases (STKs). It contains a catalytic kinase domain sandwiched in between N- and C-terminal regulatory domains. It is regulated by phosphorylation and degradation, and its expression levels are also controlled by circadian clock proteins. The fungal Wee1 subfamily is part of a larger superfamily that includes the catalytic domains of STKs, other PTKs, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20
                 ....*....|....*....|....*..
gi 645930265 108 DIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:cd14052  114 ELSLGLRFIHDHHFVHLDLKPANVLIT 140

Catalytic domain of the Serine/Threonine Kinases, Polo-like kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PLKs play important roles in cell cycle progression and in DNA damage responses. They regulate mitotic entry, mitotic exit, and cytokinesis. In general PLKs contain an N-terminal catalytic kinase domain and a C-terminal regulatory polo box domain (PBD), which is comprised by two bipartite polo-box motifs (or polo boxes) and is involved in protein interactions. PLKs derive their names from homology to polo, a kinase first identified in Drosophila. There are five mammalian PLKs (PLK1-5) from distinct genes. There is good evidence that PLK1 may function as an oncogene while PLK2-5 have tumor suppressive properties. PLK1 functions as a positive regulator of mitosis, meiosis, and cytokinesis. PLK2 functions in G1 progression, S-phase arrest, and centriole duplication. PLK3 regulates angiogenesis and responses to DNA damage. PLK4 is required for late mitotic progression, cell survival, and embryonic development. PLK5 was first identified as a pseudogene containing a stop codon within the kinase domain, however, both murine and human genes encode expressed proteins. PLK5 functions in cell cycle arrest.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 645930265   5 GATVAVKQVKKCSKNSLASRQSFWAELNVaH--LDHNNVVRVVAAStcspasQDSVGT-IIMEYVGISTLHHIIygtdcK 81
Cdd:cd14099   26 GKVYAGKVVPKSSLTKPKQREKLKSEIKI-HrsLKHPNIVKFHDCF------EDEENVyILLELCSNGSLMELL-----K 93

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 645930265  82 IAKwkdvglggvhvPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:cd14099   94 RRK-----------ALTEPEVRYFMRQILSGVKYLHSNRIIHRDLKLGNLFLD 135

Catalytic domain of the Serine/Threonine Kinase, Cyclin-Dependent protein Kinase 6; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CDK6 is regulated by D-type cyclins and INK4 inhibitors. It is active towards the retinoblastoma (pRb) protein, implicating it to function in regulating the early G1 phase of the cell cycle. It is expressed ubiquitously and is localized in the cytoplasm. It is also present in the ruffling edge of spreading fibroblasts and may play a role in cell spreading. It binds to the p21 inhibitor without any effect on its own activity and it is overexpressed in squamous cell carcinomas and neuroblastomas. CDK6 has also been shown to inhibit cell differentiation in many cell types. 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 CDK6 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 645930265  36 LDHNNVVRVVAASTCSPASQDSVGTIIMEyvgistlhHIIYGTDCKIAKWKDVGlggvhVPLSITEALRYScdIAAGLVF 115
Cdd:cd07862   61 FEHPNVVRLFDVCTVSRTDRETKLTLVFE--------HVDQDLTTYLDKVPEPG-----VPTETIKDMMFQ--LLRGLDF 125

                         90
                 ....*....|....*....
gi 645930265 116 LHSHLIVHLDLKPANIFIT 134
Cdd:cd07862  126 LHSHRVVHRDLKPQNILVT 144

Catalytic domain of AMP-activated protein kinase-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The AMPK-like subfamily is composed of AMPK, MARK, BRSK, NUAK, MELK, SNRK, TSSK, and SIK, among others. LKB1 serves as a master upstream kinase that activates AMPK and most AMPK-like kinases. AMPK, also called SNF1 (sucrose non-fermenting1) in yeasts and SnRK1 (SNF1-related kinase1) in plants, is a heterotrimeric enzyme composed of a catalytic alpha subunit and two regulatory subunits, beta and gamma. It is a stress-activated kinase that serves as master regulator of glucose and lipid metabolism by monitoring carbon and energy supplies, via sensing the cell's AMP:ATP ratio. MARKs phosphorylate tau and related microtubule-associated proteins (MAPs), and regulates microtubule-based intracellular transport. They are involved in embryogenesis, epithelial cell polarization, cell signaling, and neuronal differentiation. BRSKs play important roles in establishing neuronal polarity. TSSK proteins are almost exclusively expressed postmeiotically in the testis and play important roles in spermatogenesis and/or spermiogenesis. The AMPK-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 645930265   5 GATVAVKQVKKcSKNSLASRQSFWAELNV-AHLDHNNVVR---VVAastcspaSQDSVGtIIMEYVGISTLHHIIYGtdc 80
Cdd:cd14003   25 GEKVAIKIIDK-SKLKEEIEEKIKREIEImKLLNHPNIIKlyeVIE-------TENKIY-LVMEYASGGELFDYIVN--- 92

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 645930265  81 kiakwkdvglggvHVPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFI 133
Cdd:cd14003   93 -------------NGRLSEDEARRFFQQLISAVDYCHSNGIVHRDLKLENILL 132

Pseudokinase domain, repeat 1, of eukaryotic translation Initiation Factor 2-Alpha Kinase 4 or General Control Non-derepressible-2; The pseudokinase domain shows similarity to protein kinases but lacks crucial residues for catalytic activity. EIF2AKs phosphorylate the alpha subunit of eIF-2, resulting in the overall downregulation of protein synthesis. eIF-2 phosphorylation is induced in response to cellular stresses including virus infection, heat shock, nutrient deficiency, and the accummulation of unfolded proteins, among others. There are four distinct kinases that phosphorylate eIF-2 and control protein synthesis under different stress conditions: GCN2, protein kinase regulated by RNA (PKR), heme-regulated inhibitor kinase (HRI), and PKR-like endoplasmic reticulum kinase (PERK). GCN2 is activated by amino acid or serum starvation and UV irradiation. It induces GCN4, a transcriptional activator of amino acid biosynthetic genes, leading to increased production of amino acids under amino acid-deficient conditions. In serum-starved cells, GCN2 activation induces translation of the stress-responsive transcription factor ATF4, while under UV stress, GCN2 triggers transcriptional rescue via NF-kappaB signaling. GCN2 contains an N-terminal RWD, a degenerate kinase-like (repeat 1), the catalytic kinase (repeat 2), a histidyl-tRNA synthetase (HisRS)-like, and a C-terminal ribosome-binding and dimerization (RB/DD) domains. The degenerate pseudokinase domain of GCN2 may function as a regulatory domain. The GCN2 subfamily is part of a larger superfamily that includes the catalytic domains of serine/threonine kinases, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 645930265   7 TVAVKQVKKCSKNSLASRQSFWAELN-VAHLDHNNVVRVVAaSTCSPASQDSVGTI--IMEYVGISTLHHIIygtdckia 83
Cdd:cd14012   25 KFLTSQEYFKTSNGKKQIQLLEKELEsLKKLRHPNLVSYLA-FSIERRGRSDGWKVylLTEYAPGGSLSELL-------- 95

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 645930265  84 kwkdvglgGVHVPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFI 133
Cdd:cd14012   96 --------DSVGSVPLDTARRWTLQLLEALEYLHRNGVVHKSLHAGNVLL 137

Pseudokinase domain of the unknown subfamily of membrane Guanylate Cyclase receptors; The pseudokinase domain shows similarity to protein kinases but lacks crucial residues for catalytic activity. Membrane (or particulate) GCs consist of an extracellular ligand-binding domain, a single transmembrane region, and an intracellular tail that contains a PK-like domain, an amphiphatic region and a catalytic GC domain that catalyzes the conversion of GTP into cGMP and pyrophosphate. Membrane GCs act as receptors that transduce an extracellular signal to the intracellular production of cGMP, which has been implicated in many processes including cell proliferation, phototransduction, and muscle contractility, through its downstream effectors such as PKG. The PK-like domain of GCs lack a critical aspartate involved in ATP binding and does not exhibit kinase activity. It functions as a negative regulator of the catalytic GC domain and may also act as a docking site for interacting proteins such as GC-activating proteins. The GC subfamily is part of a larger superfamily that includes the catalytic domains of protein serine/threonine kinases, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 645930265   2 IYQGATVAVKQVkkcSKNSLASRQSFWAEL-NVAHLDHNNVVRVVAASTCSPASqdsvgTIIMEYVGISTLHHIIYGTDc 80
Cdd:cd14045   27 IYDGRTVAIKKI---AKKSFTLSKRIRKEVkQVRELDHPNLCKFIGGCIEVPNV-----AIITEYCPKGSLNDVLLNED- 97

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 645930265  81 kiakwkdvglggvhVPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFI 133
Cdd:cd14045   98 --------------IPLNWGFRFSFATDIARGMAYLHQHKIYHGRLKSSNCVI 136

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 645930265   9 AVKQVKKCSKNSLASRQSFWAELNV-AHLDHNNVVRVVAASTcspaSQDSVGtIIMEYVGISTLHHIIYGtdckiakwkd 87
Cdd:cd05123   22 AMKVLRKKEIIKRKEVEHTLNERNIlERVNHPFIVKLHYAFQ----TEEKLY-LVLDYVPGGELFSHLSK---------- 86

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 645930265  88 vglggvHVPLSITEALRYSCDIAAGLVFLHSHLIVHLDLKPANIFIT 134
Cdd:cd05123   87 ------EGRFPEERARFYAAEIVLALEYLHSLGIIYRDLKPENILLD 127