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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133343    57 LLQPLGSGGFGSVYKATYH--GATVAVKQVKKssKNRLASRQSFWAELNV-ARLQHANVVRVVAASTcapaSQNSLgTII 133
Cdd:smart00220   3 ILEKLGEGSFGKVYLARDKktGKLVAIKVIKK--KKIKKDRERILREIKIlKKLKHPNIVRLYDVFE----DEDKL-YLV 75

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133343   134 MEYVGNITL**VIygtsdtwrqgeedeggCGKKALSLEETVCYSCDILSGLAFLHSQGIV 193
Cdd:smart00220  76 MEYCEGGDLFDLL----------------KKRGRLSEDEARFYLRQILSALEYLHSKGIV 119

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 405133343   55 LCLLQPLGSGGFGSVYKATYHGA------TVAVKQVKKSSKNRlaSRQSFWAELNV-ARLQHANVVRVVAASTCAPASQn 127
Cdd:pfam07714   1 LTLGEKLGEGAFGEVYKGTLKGEgentkiKVAVKTLKEGADEE--EREDFLEEASImKKLDHPNIVKLLGVCTQGEPLY- 77

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 405133343  128 slgtIIMEYVgnitl**viygtsdtwrqgeedEGGC-------GKKALSLEETVCYSCDILSGLAFLHSQGIV 193
Cdd:pfam07714  78 ----IVTEYM----------------------PGGDlldflrkHKRKLTLKDLLSMALQIAKGMEYLESKNFV 124

Catalytic domain of Protein Kinases; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine or tyrosine residues on protein substrates. PKs make up a large family of serine/threonine kinases (STKs), protein tyrosine kinases (PTKs), and dual-specificity PKs that phosphorylate both serine/threonine and tyrosine residues of target proteins. Majority of protein phosphorylation occurs on serine residues while only 1% occurs on tyrosine residues. Protein phosphorylation is a mechanism by which a wide variety of cellular proteins, such as enzymes and membrane channels, are reversibly regulated in response to certain stimuli. PKs often function as components of signal transduction pathways in which one kinase activates a second kinase, which in turn, may act on other kinases; this sequential action transmits a signal from the cell surface to target proteins, which results in cellular responses. The PK family is one of the largest known protein families with more than 100 homologous yeast enzymes and more than 500 human proteins. A fraction of PK family members are pseudokinases that lack crucial residues for catalytic activity. The mutiplicity of kinases allows for specific regulation according to substrate, tissue distribution, and cellular localization. PKs regulate many cellular processes including proliferation, division, differentiation, motility, survival, metabolism, cell-cycle progression, cytoskeletal rearrangement, immunity, and neuronal functions. Many kinases are implicated in the development of various human diseases including different types of cancer. The PK family is part of a larger superfamily that includes the catalytic domains of RIO kinases, aminoglycoside phosphotransferase, choline kinase, phosphoinositide 3-kinase (PI3K), and actin-fragmin kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133343  61 LGSGGFGSVYKATY--HGATVAVKQVKKSSKNRLasRQSFWAELNV-ARLQHANVVRVVAASTcapaSQNSLGtIIMEYV 137
Cdd:cd00180    1 LGKGSFGKVYKARDkeTGKKVAVKVIPKEKLKKL--LEELLREIEIlKKLNHPNIVKLYDVFE----TENFLY-LVMEYC 73

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 405133343 138 GNITL**VIygtsdtwrqgEEDEGGcgkkaLSLEETVCYSCDILSGLAFLHSQGIV 193
Cdd:cd00180   74 EGGSLKDLL----------KENKGP-----LSEEEALSILRQLLSALEYLHSNGII 114

Serine/threonine protein kinase [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133343  57 LLQPLGSGGFGSVYKATYH--GATVAVKQVKKSSKNRLASRQSFWAELNV-ARLQHANVVRVVAASTcapasQNSLGTII 133
Cdd:COG0515   11 ILRLLGRGGMGVVYLARDLrlGRPVALKVLRPELAADPEARERFRREARAlARLNHPNIVRVYDVGE-----EDGRPYLV 85

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133343 134 MEYVGNITL**VIygtsdtwrqgeeDEGGcgkkALSLEETVCYSCDILSGLAFLHSQGIV 193
Cdd:COG0515   86 MEYVEGESLADLL------------RRRG----PLPPAEALRILAQLAEALAAAHAAGIV 129

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 405133343  61 LGSGGFGSVYKATYHGATVAVKQVKKSSKNRLASRQsFWAELNV-ARLQHANVVRVVAASTcapaSQNSLgTIIMEYVGN 139
Cdd:cd13999    1 IGSGSFGEVYKGKWRGTDVAIKKLKVEDDNDELLKE-FRREVSIlSKLRHPNIVQFIGACL----SPPPL-CIVTEYMPG 74

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 405133343 140 ITL**VIYGTsdtwrqgeedeggcgKKALSLEETVCYSCDILSGLAFLHSQGIV 193
Cdd:cd13999   75 GSLYDLLHKK---------------KIPLSWSLRLKIALDIARGMNYLHSPPII 113

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 405133343   55 LCLLQPLGSGGFGSVYKATYHGA------TVAVKQVKKSSKNRlaSRQSFWAELNV-ARLQHANVVRVVAASTCAPASQn 127
Cdd:pfam07714   1 LTLGEKLGEGAFGEVYKGTLKGEgentkiKVAVKTLKEGADEE--EREDFLEEASImKKLDHPNIVKLLGVCTQGEPLY- 77

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 405133343  128 slgtIIMEYVgnitl**viygtsdtwrqgeedEGGC-------GKKALSLEETVCYSCDILSGLAFLHSQGIV 193
Cdd:pfam07714  78 ----IVTEYM----------------------PGGDlldflrkHKRKLTLKDLLSMALQIAKGMEYLESKNFV 124

Catalytic domain of Cell division control protein 7-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Members of this subfamily include Schizosaccharomyces pombe Cdc7, Saccharomyces cerevisiae Cdc15, Arabidopsis thaliana mitogen-activated protein kinase kinase kinase (MAPKKK) epsilon, and related proteins. MAPKKKs phosphorylate and activate MAPK kinases, which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. Fission yeast Cdc7 is essential for cell division by playing a key role in the initiation of septum formation and cytokinesis. Budding yeast Cdc15 functions to coordinate mitotic exit with cytokinesis. Arabidopsis MAPKKK epsilon is required for pollen development in the plasma membrane. The Cdc7-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 405133343  61 LGSGGFGSVYKA--TYHGATVAVKQVKkSSKNRLASRQSFWAELNV-ARLQHANVVRVVAASTcapaSQNSLgTIIMEYV 137
Cdd:cd06627    8 IGRGAFGSVYKGlnLNTGEFVAIKQIS-LEKIPKSDLKSVMGEIDLlKKLNHPNIVKYIGSVK----TKDSL-YIILEYV 81

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 405133343 138 GNITL**VIygtsdtwrqgeedeggcgKKALSLEETVC--YSCDILSGLAFLHSQGIV 193
Cdd:cd06627   82 ENGSLASII------------------KKFGKFPESLVavYIYQVLEGLAYLHEQGVI 121

Catalytic domain of the Serine/Threonine kinases, Interleukin-1 Receptor Associated Kinases and related STKs; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. IRAKs are involved in Toll-like receptor (TLR) and interleukin-1 (IL-1) signalling pathways, and are thus critical in regulating innate immune responses and inflammation. Some IRAKs may also play roles in T- and B-cell signaling, and adaptive immunity. Vertebrates contain four IRAKs (IRAK-1, -2, -3 (or -M), and -4) that display distinct functions and patterns of expression and subcellular distribution, and can differentially mediate TLR signaling. IRAK-1, -2, and -4 are ubiquitously expressed and are active kinases, while IRAK-M is only induced in monocytes and macrophages and is an inactive kinase. Variations in IRAK genes are linked to diverse diseases including infection, sepsis, cancer, and autoimmune diseases. IRAKs contain an N-terminal Death domain (DD), a proST region (rich in serines, prolines, and threonines), a central kinase domain (a pseudokinase domain in the case of IRAK3), and a C-terminal domain; IRAK-4 lacks the C-terminal domain. This subfamily includes plant receptor-like kinases (RLKs) including Arabidopsis thaliana BAK1 and CLAVATA1 (CLV1). BAK1 functions in BR (brassinosteroid)-regulated plant development and in pathways involved in plant resistance to pathogen infection and herbivore attack. CLV1, directly binds small signaling peptides, CLAVATA3 (CLV3) and CLAVATA3/EMBRYO SURROUNDING REGI0N (CLE), to restrict stem cell proliferation: the CLV3-CLV1-WUS (WUSCHEL) module influences stem cell maintenance in the shoot apical meristem, and the CLE40 (CLAVATA3/EMBRYO SURROUNDING REGION40) -ACR4 (CRINKLY4) -CLV1- WOX5 (WUSCHEL-RELATED HOMEOBOX5) module at the root apical meristem. The IRAK 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 405133343  61 LGSGGFGSVYKATYH-GATVAVKQVKksSKNRLASRQSFWAEL-NVARLQHANVVRVVAasTCapaSQNSLGTIIMEYVG 138
Cdd:cd14066    1 IGSGGFGTVYKGVLEnGTVVAVKRLN--EMNCAASKKEFLTELeMLGRLRHPNLVRLLG--YC---LESDEKLLVYEYMP 73

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 405133343 139 NITL**VIYGTSdtwrqgeedeggcGKKALSLEETVCYSCDILSGLAFLHS 189
Cdd:cd14066   74 NGSLEDRLHCHK-------------GSPPLPWPQRLKIAKGIARGLEYLHE 111

The catalytic domain of CAMK family Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CaMKs are multifunctional calcium and calmodulin (CaM) stimulated STKs involved in cell cycle regulation. There are several types of CaMKs including CaMKI, CaMKII, and CaMKIV. CaMKI proteins are monomeric and they play pivotal roles in the nervous system, including long-term potentiation, dendritic arborization, neurite outgrowth, and the formation of spines, synapses, and axons. CaMKII is a signaling molecule that translates upstream calcium and reactive oxygen species (ROS) signals into downstream responses that play important roles in synaptic function and cardiovascular physiology. CAMKIV is implicated in regulating several transcription factors like CREB, MEF2, and retinoid orphan receptors, as well as in T-cell development and signaling. The CAMK family also consists of other related kinases including the Phosphorylase kinase Gamma subunit (PhKG), the C-terminal kinase domains of Ribosomal S6 kinase (RSK) and Mitogen and stress-activated kinase (MSK), Doublecortin-like kinase (DCKL), and the MAPK-activated protein kinases MK2, MK3, and MK5, among others. The CAMK family is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133343  57 LLQPLGSGGFGSVYKATYH--GATVAVKQVKKSsKNRLASRQSFWAELNVA-RLQHANVVRVVAAStcapASQNSLgTII 133
Cdd:cd05117    4 LGKVLGRGSFGVVRLAVHKktGEEYAVKIIDKK-KLKSEDEEMLRREIEILkRLDHPNIVKLYEVF----EDDKNL-YLV 77

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 405133343 134 MEYVgnitl**viygtsdtwrqgeedEGG------CGKKALSLEETVCYSCDILSGLAFLHSQGIV 193
Cdd:cd05117   78 MELC----------------------TGGelfdriVKKGSFSEREAAKIMKQILSAVAYLHSQGIV 121

Stk1 family PASTA domain-containing Ser/Thr kinase;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133343  57 LLQPLGSGGFGSVYKA--TYHGATVAVKqVKKSSknrLASRQSFWA----E-LNVARLQHANVVRV--VAastcapaSQN 127
Cdd:NF033483  11 IGERIGRGGMAEVYLAkdTRLDRDVAVK-VLRPD---LARDPEFVArfrrEaQSAASLSHPNIVSVydVG-------EDG 79

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 405133343 128 SLGTIIMEYVGNITL**VIygtsdtwrqgeeDEGGcgkkALSLEETVCYSCDILSGLAFLHSQGIV 193
Cdd:NF033483  80 GIPYIVMEYVDGRTLKDYI------------REHG----PLSPEEAVEIMIQILSALEHAHRNGIV 129

Catalytic domain of the Serine/Threonine kinases, Liver Kinase B1, Calmodulin Dependent Protein Kinase Kinase, and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Both LKB1 and CaMKKs can phosphorylate and activate AMP-activated protein kinase (AMPK). LKB1, also called STK11, serves as a master upstream kinase that activates AMPK and most AMPK-like kinases. LKB1 and AMPK are part of an energy-sensing pathway that links cell energy to metabolism and cell growth. They play critical roles in the establishment and maintenance of cell polarity, cell proliferation, cytoskeletal organization, as well as T-cell metabolism, including T-cell development, homeostasis, and effector function. CaMKKs are upstream kinases of the CaM kinase cascade that phosphorylate and activate CaMKI and CamKIV. They may also phosphorylate other substrates including PKB and AMPK. Vertebrates contain two CaMKKs, CaMKK1 (or alpha) and CaMKK2 (or beta). CaMKK1 is involved in the regulation of glucose uptake in skeletal muscles. CaMKK2 is involved in regulating energy balance, glucose metabolism, adiposity, hematopoiesis, inflammation, and cancer. The LKB1/CaMKK 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 405133343  61 LGSGGFGSVYKA--TYHGATVAVKQVKKSSKNRLASRQSFWAELNVA------------RLQHANVVRVVAAstCAPASQ 126
Cdd:cd14008    1 LGRGSFGKVKLAldTETGQLYAIKIFNKSRLRKRREGKNDRGKIKNAlddvrreiaimkKLDHPNIVRLYEV--IDDPES 78

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 405133343 127 NSLgTIIMEYVGNITL**viygtsdtwrqgEEDEGGCGKKALSLEETVCYSCDILSGLAFLHSQGIV 193
Cdd:cd14008   79 DKL-YLVLEYCEGGPV--------------MELDSGDRVPPLPEETARKYFRDLVLGLEYLHENGIV 130

Catalytic domain of Fungal Halotolerance protein 4-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 HAL4, Saccharomyces cerevisiae Ptk2/Stk2, and similar fungal proteins. Proteins in this subfamily are involved in regulating ion transporters. In budding and fission yeast, HAL4 promotes potassium ion uptake, which increases cellular resistance to other cations such as sodium, lithium, and calcium ions. HAL4 stabilizes the major high-affinity K+ transporter Trk1 at the plasma membrane under low K+ conditions, which prevents endocytosis and vacuolar degradation. Budding yeast Ptk2 phosphorylates and regulates the plasma membrane H+ ATPase, Pma1. The HAL4-like 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 405133343  61 LGSGGFGSV----YKATYHGATVAVKQVKKSSKNRLAS--RQSFWAELNVAR-LQHANVVRVVaastCAPASQNSLGTII 133
Cdd:cd13994    1 IGKGATSVVrivtKKNPRSGVLYAVKEYRRRDDESKRKdyVKRLTSEYIISSkLHHPNIVKVL----DLCQDLHGKWCLV 76

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133343 134 MEYVGNITL**VIygtsdtwrqgEEDeggcgkKALSLEETVCYSCDILSGLAFLHSQGIV 193
Cdd:cd13994   77 MEYCPGGDLFTLI----------EKA------DSLSLEEKDCFFKQILRGVAYLHSHGIA 120

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 405133343  58 LQPLGSGGFGSVYKA--TYHGATVAVKQVKKSSKNRLASRqsFWAELN-VARLQHANVVRVVAASTcapasQNSLGTIIM 134
Cdd:cd14046   11 LQVLGKGAFGQVVKVrnKLDGRYYAIKKIKLRSESKNNSR--ILREVMlLSRLNHQHVVRYYQAWI-----ERANLYIQM 83

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 405133343 135 EYVGNITL**VI-----YGTSDTWRQGEEdeggcgkkalsleetvcyscdILSGLAFLHSQGIV 193
Cdd:cd14046   84 EYCEKSTLRDLIdsglfQDTDRLWRLFRQ---------------------ILEGLAYIHSQGII 126

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 405133343  61 LGSGGFGSVYKAT--YHGATVAVKQVKKSSKNRLASRQSFWAELNV-ARLQHANVVRVVAastCAPASQNSLgtIIMEYV 137
Cdd:cd14099    9 LGKGGFAKCYEVTdmSTGKVYAGKVVPKSSLTKPKQREKLKSEIKIhRSLKHPNIVKFHD---CFEDEENVY--ILLELC 83

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 405133343 138 GNITL**viygtsDTWRQgeedeggcgKKALSLEETVCYSCDILSGLAFLHSQGIV 193
Cdd:cd14099   84 SNGSLM-------ELLKR---------RKALTEPEVRYFMRQILSGVKYLHSNRII 123

Catalytic domain of the Serine/Threonine Kinase, Leucine-Rich Repeat Kinase 2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. LRRK2 is one of two vertebrate LRRKs which show complementary expression in the brain. Mutations in LRRK2, found in the kinase, ROC-COR, and WD40 domains, are linked to both familial and sporadic forms of Parkinson's disease. The most prevalent mutation, G2019S located in the activation loop of the kinase domain, increases kinase activity. The R1441C/G mutations in the GTPase domain have also been reported to influence kinase activity. LRRKs are also classified as ROCO proteins because they contain a ROC (Ras of complex proteins)/GTPase domain followed by a COR (C-terminal of ROC) domain of unknown function. In addition, LRRKs contain a catalytic kinase domain and protein-protein interaction motifs including a WD40 domain, LRRs and ankyrin (ANK) repeats. LRRKs possess both GTPase and kinase activities, with the ROC domain acting as a molecular switch for the kinase domain, cycling between a GTP-bound state which drives kinase activity and a GDP-bound state which decreases the activity. The LRRK2 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 405133343  61 LGSGGFGSVYKATYHGATVAVKQVKKSSKNRLAsRQsfwaELNV-ARLQHANVVRVVAASTCAPAsqnslgtIIMEYVGN 139
Cdd:cd14068    2 LGDGGFGSVYRAVYRGEDVAVKIFNKHTSFRLL-RQ----ELVVlSHLHHPSLVALLAAGTAPRM-------LVMELAPK 69

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 405133343 140 ITL**VIygtsdtwrqgEEDEGGCGKKalsLEETVcySCDILSGLAFLHSQGIV 193
Cdd:cd14068   70 GSLDALL----------QQDNASLTRT---LQHRI--ALHVADGLRYLHSAMII 108

Catalytic domain of the Serine/Threonine Kinase, Transforming Growth Factor beta Activated Kinase-1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. TAK1 is also known as mitogen-activated protein kinase kinase kinase 7 (MAPKKK7 or MAP3K7), TAK, or MEKK7. As a MAPKKK, it is an important mediator of cellular responses to extracellular signals. It regulates both the c-Jun N-terminal kinase and p38 MAPK cascades by activating the MAPK kinases, MKK4 and MKK3/6. In addition, TAK1 plays diverse roles in immunity and development, in different biological contexts, through many signaling pathways including TGFbeta/BMP, Wnt/Fz, and NF-kB. It is also implicated in the activation of the tumor suppressor kinase, LKB1. The TAK1 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 405133343  61 LGSGGFGSVYKATYHGATVAVKQVKKSSKnrlasRQSFWAEL-NVARLQHANVVRVVAASTCAPASqnslgTIIMEYVGN 139
Cdd:cd14058    1 VGRGSFGVVCKARWRNQIVAVKIIESESE-----KKAFEVEVrQLSRVDHPNIIKLYGACSNQKPV-----CLVMEYAEG 70

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 405133343 140 ITL**VIYGTSDTWrqgeedeggcgkkALSLEETVCYSCDILSGLAFLHS 189
Cdd:cd14058   71 GSLYNVLHGKEPKP-------------IYTAAHAMSWALQCAKGVAYLHS 107

Catalytic domain of the Serine/Threonine Kinases, Mitogen-Activated Protein Kinase Kinase Kinases 12 and 13; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MAP3K12 is also called MAPK upstream kinase (MUK), dual leucine zipper-bearing kinase (DLK) or leucine-zipper protein kinase (ZPK). It is involved in the c-Jun N-terminal kinase (JNK) pathway that directly regulates axonal regulation through the phosphorylation of microtubule-associated protein 1B (MAP1B). It also regulates the differentiation of many cell types including adipocytes and may play a role in adipogenesis. MAP3K13, also called leucine zipper-bearing kinase (LZK), directly phosphorylates and activates MKK7, which in turn activates the JNK pathway. It also activates NF-kB through IKK activation and this activity is enhanced by antioxidant protein-1 (AOP-1). MAP3Ks (MKKKs or MAPKKKs) phosphorylate and activate MAP2Ks (MAPKKs or MKKs), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. The MAP3K12/13 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 405133343  61 LGSGGFGSVYKATYHGATVAVKQVKKSSKNRLAsrqsfwaelNVARLQHANVVRVVAASTCAPASqnslgTIIMEYVGNI 140
Cdd:cd14059    1 LGSGAQGAVFLGKFRGEEVAVKKVRDEKETDIK---------HLRKLNHPNIIKFKGVCTQAPCY-----CILMEYCPYG 66

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 405133343 141 TL**VIygtsdtwRQGEEdeggcgkkaLSLEETVCYSCDILSGLAFLHSQGIV 193
Cdd:cd14059   67 QLYEVL-------RAGRE---------ITPSLLVDWSKQIASGMNYLHLHKII 103

Catalytic domain of Cyclin-Dependent protein Kinase 9-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 CDK9 and CDK12 from higher eukaryotes, yeast BUR1, C-type plant CDKs (CdkC), and similar proteins. CDK9, BUR1, and CdkC are functionally equivalent. They act as a kinase for the C-terminal domain of RNA polymerase II and participate in regulating mutliple steps of gene expression including transcription elongation and RNA processing. CDK9 and CdkC associate with T-type cyclins while BUR1 associates with the cyclin BUR2. CDK12 is a unique CDK that contains an arginine/serine-rich (RS) domain, which is predominantly found in splicing factors. CDK12 interacts with cyclins L1 and L2, and participates in regulating transcription and alternative splicing. 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 CDK9-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 405133343  61 LGSGGFGSVYKA--TYHGATVAVKQVKKSSKN----RLASRqsfwaELNVAR-LQHANVVRVVAASTcAPASQNSLGTII 133
Cdd:cd07840    7 IGEGTYGQVYKArnKKTGELVALKKIRMENEKegfpITAIR-----EIKLLQkLDHPNVVRLKEIVT-SKGSAKYKGSIY 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 405133343 134 M--EYVgnitl**viygtsdtwrqgEEDEGG---CGKKALSLEETVCYSCDILSGLAFLHSQGIV 193
Cdd:cd07840   81 MvfEYM-------------------DHDLTGlldNPEVKFTESQIKCYMKQLLEGLQYLHSNGIL 126

Catalytic domain of the LIM domain kinase-like protein kinases; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine or tyrosine residues on protein substrates. Members of this subfamily include LIMK, Testicular or testis-specific protein kinase (TESK), and similar proteins. LIMKs are characterized as serine/threonine kinases (STKs) while TESKs are dual-specificity protein kinases. Both LIMK and TESK phosphorylate and inactivate cofilin, an actin depolymerizing factor, to induce the reorganization of the actin cytoskeleton. They are implicated in many cellular functions including cell spreading, motility, morphogenesis, meiosis, mitosis, and spermatogenesis. The LIMK-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 405133343  61 LGSGGFGSVYKATyHGATVAVKQVKKSSknRLASRQSFWAELNVAR-LQHANVVRVVAasTCAPASQNSLgtiIMEYVGN 139
Cdd:cd14065    1 LGKGFFGEVYKVT-HRETGKVMVMKELK--RFDEQRSFLKEVKLMRrLSHPNILRFIG--VCVKDNKLNF---ITEYVNG 72

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 405133343 140 ITL**VIYGTSDTwrqgeedeggcgkkaLSLEETVCYSCDILSGLAFLHSQGIV 193
Cdd:cd14065   73 GTLEELLKSMDEQ---------------LPWSQRVSLAKDIASGMAYLHSKNII 111

Catalytic domain of the Serine/Threonine kinase, Interleukin-1 Receptor Associated Kinase 4; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. IRAKs are involved in Toll-like receptor (TLR) and interleukin-1 (IL-1) signalling pathways, and are thus critical in regulating innate immune responses and inflammation. IRAKs contain an N-terminal Death domain (DD), a proST region (rich in serines, prolines, and threonines), a central kinase domain, and a C-terminal domain; IRAK-4 lacks the C-terminal domain. Vertebrates contain four IRAKs (IRAK-1, -2, -3 (or -M), and -4) that display distinct functions and patterns of expression and subcellular distribution, and can differentially mediate TLR signaling. IRAK4 plays a critical role in NFkB activation by its interaction with MyD88, which acts as a scaffold that enables IRAK4 to phosphorylate and activate IRAK1 and/or IRAK2. It also plays an important role in type I IFN production induced by TLR7/8/9. The IRAK4 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 405133343  61 LGSGGFGSVYKATYHGATVAVKQVKKSSKNRLAS-RQSFWAELNV-ARLQHANVVRVVAASTCAPASqnslgTIIMEYVG 138
Cdd:cd14158   23 LGEGGFGVVFKGYINDKNVAVKKLAAMVDISTEDlTKQFEQEIQVmAKCQHENLVELLGYSCDGPQL-----CLVYTYMP 97

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 405133343 139 NITL**viygtsdtwrqgeEDEGGCGKKALSLeeTVCYSCDILSGLA----FLHSQGIV 193
Cdd:cd14158   98 NGSL---------------LDRLACLNDTPPL--SWHMRCKIAQGTAnginYLHENNHI 139

Catalytic domain of the Protein Tyrosine Kinases, Vascular Endothelial Growth Factor Receptors; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The VEGFR subfamily consists of VEGFR1 (Flt1), VEGFR2 (Flk1), VEGFR3 (Flt4), and similar proteins. VEGFR subfamily members are receptor PTKss (RTKs) containing an extracellular ligand-binding region with seven immunoglobulin (Ig)-like domains, a transmembrane segment, and an intracellular catalytic domain. In VEGFR3, the fifth Ig-like domain is replaced by a disulfide bridge. The binding of VEGFRs to their ligands, the VEGFs, leads to receptor dimerization, activation, and intracellular signaling. There are five VEGF ligands in mammals, which bind, in an overlapping pattern to the three VEGFRs, which can form homo or heterodimers. VEGFRs regulate the cardiovascular system. They are critical for vascular development during embryogenesis and blood vessel formation in adults. They induce cellular functions common to other growth factor receptors such as cell migration, survival, and proliferation. The VEGFR 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 405133343  53 EQLCLLQPLGSGGFGSVYKATYHG-------ATVAVKQVKKSSknRLASRQSFWAELNVARL--QHANVVRVVAASTcap 123
Cdd:cd05054    7 DRLKLGKPLGRGAFGKVIQASAFGidksatcRTVAVKMLKEGA--TASEHKALMTELKILIHigHHLNVVNLLGACT--- 81

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 405133343 124 aSQNSLGTIIMEYV--GNITL-------**VIYGTSDTWR-QGEEDEGGCGKKALSLEETVCYSCDILSGLAFLHSQ 190
Cdd:cd05054   82 -KPGGPLMVIVEFCkfGNLSNylrskreEFVPYRDKGARDvEEEEDDDELYKEPLTLEDLICYSFQVARGMEFLASR 157

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 405133343  57 LLQPLGSGGFGSVYKAtYH---GATVAVKQVKKSSKNRLASRQsFWAELNVAR-LQHANVVR---VVAastcapaSQNSL 129
Cdd:cd14003    4 LGKTLGEGSFGKVKLA-RHkltGEKVAIKIIDKSKLKEEIEEK-IKREIEIMKlLNHPNIIKlyeVIE-------TENKI 74

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 405133343 130 GtIIMEYVGNITL**VIygtsdtwrqgeedeggCGKKALSLEETVCYSCDILSGLAFLHSQGIV 193
Cdd:cd14003   75 Y-LVMEYASGGELFDYI----------------VNNGRLSEDEARRFFQQLISAVDYCHSNGIV 121

Catalytic domain of the Serine/Threonine kinases, Autophagy-related protein 1 and Unc-51-like kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily includes yeast ATG1 and metazoan homologs including vertebrate ULK1-3. The ATG1/ULK complex is conserved from yeast to humans and it plays a critical role in the initiation of autophagy, the intracellular system that leads to the lysosomal degradation of cellular components and their recycling into basic metabolic units. It is involved in nutrient sensing and signaling, the assembly of autophagy factors and the execution of autophagy. In metazoans, ATG1 homologs display additional functions. Unc-51 and ULKs have been implicated in neuronal and axonal development. The ATG1/ULK 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 405133343  61 LGSGGFGSVYKATY--HGATVAVKQVKKSSKNRlASRQSFWAELNVAR-LQHANVVRVVAAstcapasQNSLGTI--IME 135
Cdd:cd14009    1 IGRGSFATVWKGRHkqTGEVVAIKEISRKKLNK-KLQENLESEIAILKsIKHPNIVRLYDV-------QKTEDFIylVLE 72

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133343 136 YVGNITL**VIygtsdtwrqgeedeggcgKKALSLEETV--CYSCDILSGLAFLHSQGIV 193
Cdd:cd14009   73 YCAGGDLSQYI------------------RKRGRLPEAVarHFMQQLASGLKFLRSKNII 114