Protein Kinase B-like pleckstrin homology (PH) domain; PKB (also called Akt), a member of the AGC kinase family, is a phosphatidylinositol 3'-kinase (PI3K)-dependent Ser/Thr kinase which alters the activity of the targeted protein. The name AGC is based on the three proteins that it is most similar to cAMP-dependent protein kinase 1 (PKA; also known as PKAC), cGMP-dependent protein kinase (PKG; also known as CGK1) and protein kinase C (PKC). Human Akt has three isoforms derived for distinct genes: Akt1/PKBalpha, Akt2/PKBbeta, and Akt3/PKBgamma. All Akts have an N-terminal PH domain with an activating Thr phosphorylation site, a kinase domain, and a short C-terminal regulatory tail with an activating Ser phosphorylation site. The PH domain recruits Akt to the plasma membrane by binding to phosphoinositides (PtdIns-3,4-P2) and is required for activation. The phosphorylation of Akt at its Thr and Ser phosphorylation sites leads to increased Akt activity toward forkhead transcription factors, the mammalian target of rapamycin (mTOR), and the Bcl-xL/Bcl-2-associated death promoter (BAD), all of which possess a consensus motif R-X-R-XX-ST-B (X = amino acid, B = bulky hydrophobic residue) for Akt phosphorylation. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370451447   4 VTIVKEGWVQKRGEYIKNWRPRYFLLKTDGSFIGYKEKPQDVDLPYPLNNFSVAKCQLMKTERPKPNTFIIRCLQWTTVI 83
Cdd:cd01241     1 VSVVKEGWLLKRGEYIKNWRPRYFVLKSDGSFIGYKEKPKPNQDPPPLNNFSVAECQLMKTEKPKPNTFIIRCLQWTTVI 80

                          90       100
                  ....*....|....*....|....*..
gi 1370451447  84 ERTFHVDTPEEREEWTEAIQAVADRLQ 110
Cdd:cd01241    81 ERTFHVESEEEREEWMKAIQGVASSLK 107

Protein Kinase B-like pleckstrin homology (PH) domain; PKB (also called Akt), a member of the AGC kinase family, is a phosphatidylinositol 3'-kinase (PI3K)-dependent Ser/Thr kinase which alters the activity of the targeted protein. The name AGC is based on the three proteins that it is most similar to cAMP-dependent protein kinase 1 (PKA; also known as PKAC), cGMP-dependent protein kinase (PKG; also known as CGK1) and protein kinase C (PKC). Human Akt has three isoforms derived for distinct genes: Akt1/PKBalpha, Akt2/PKBbeta, and Akt3/PKBgamma. All Akts have an N-terminal PH domain with an activating Thr phosphorylation site, a kinase domain, and a short C-terminal regulatory tail with an activating Ser phosphorylation site. The PH domain recruits Akt to the plasma membrane by binding to phosphoinositides (PtdIns-3,4-P2) and is required for activation. The phosphorylation of Akt at its Thr and Ser phosphorylation sites leads to increased Akt activity toward forkhead transcription factors, the mammalian target of rapamycin (mTOR), and the Bcl-xL/Bcl-2-associated death promoter (BAD), all of which possess a consensus motif R-X-R-XX-ST-B (X = amino acid, B = bulky hydrophobic residue) for Akt phosphorylation. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370451447   4 VTIVKEGWVQKRGEYIKNWRPRYFLLKTDGSFIGYKEKPQDVDLPYPLNNFSVAKCQLMKTERPKPNTFIIRCLQWTTVI 83
Cdd:cd01241     1 VSVVKEGWLLKRGEYIKNWRPRYFVLKSDGSFIGYKEKPKPNQDPPPLNNFSVAECQLMKTEKPKPNTFIIRCLQWTTVI 80

                          90       100
                  ....*....|....*....|....*..
gi 1370451447  84 ERTFHVDTPEEREEWTEAIQAVADRLQ 110
Cdd:cd01241    81 ERTFHVESEEEREEWMKAIQGVASSLK 107

protein kinase A catalytic subunit; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370451447 133 MDASTTHHKRKT----MNDFDYLKLLGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVLKNTRHPFL 208
Cdd:PTZ00263    1 MKAAYMFTKPDTsswkLSDFEMGETLGTGSFGRVRIAKHKGTGEYYAIKCLKKREILKMKQVQHVAQEKSILMELSHPFI 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1370451447 209 TSLKYSFQTKDRLCFVMEYVNGGELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:PTZ00263   81 VNMMCSFQDENRVYFLLEFVVGGELFTHLRKAGRFPNDVAKFYHAELVLAFEYLHSKDIIYRDLK 145

Serine/threonine protein kinase [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370451447 151 LKLLGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEYVNG 230
Cdd:COG0515    12 LRLLGRGGMGVVYLARDLRLGRPVALKVLRPELAADPEARERFRREARALARLNHPNIVRVYDVGEEDGRPYLVMEYVEG 91

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1370451447 231 GELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:COG0515    92 ESLADLLRRRGPLPPAEALRILAQLAEALAAAHAAGIVHRDIK 134

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370451447    6 IVKEGWVQKRGE-YIKNWRPRYFLLkTDGSFIGYKEKPQDVDL----PYPLNNFSVAKCqLMKTERPKPNTFIIRCLQWT 80
Cdd:smart00233   1 VIKEGWLYKKSGgGKKSWKKRYFVL-FNSTLLYYKSKKDKKSYkpkgSIDLSGCTVREA-PDPDSSKKPHCFEIKTSDRK 78

                           90       100
                   ....*....|....*....|....*..
gi 1370451447   81 TVIertFHVDTPEEREEWTEAIQAVAD 107
Cdd:smart00233  79 TLL---LQAESEEEREKWVEALRKAIA 102

Catalytic domain of the Serine/Threonine Kinase, Protein Kinase B; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. There are three PKB isoforms from different genes, PKB-alpha (or Akt1), PKB-beta (or Akt2), and PKB-gamma (or Akt3). PKB contains an N-terminal pleckstrin homology (PH) domain and a C-terminal catalytic domain. It is activated downstream of phosphoinositide 3-kinase (PI3K) and plays important roles in diverse cellular functions including cell survival, growth, proliferation, angiogenesis, motility, and migration. PKB also has a central role in a variety of human cancers, having been implicated in tumor initiation, progression, and metastasis. The PKB 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 PI3K.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370451447 152 KLLGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEYVNGG 231
Cdd:cd05571     1 KVLGKGTFGKVILCREKATGELYAIKILKKEVIIAKDEVAHTLTENRVLQNTRHPFLTSLKYSFQTNDRLCFVMEYVNGG 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1370451447 232 ELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05571    81 ELFFHLSRERVFSEDRTRFYGAEIVLALGYLHSQGIVYRDLK 122

Catalytic domain of the Serine/Threonine Kinase, Protein Kinase B alpha (also called Akt1); STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PKB-alpha is predominantly expressed in endothelial cells. It is critical for the regulation of angiogenesis and the maintenance of vascular integrity. It also plays a role in adipocyte differentiation. Mice deficient in PKB-alpha exhibit perinatal morbidity, growth retardation, reduction in body weight accompanied by reduced sizes of multiple organs, and enhanced apoptosis in some cell types. PKB-alpha activity has been reported to be frequently elevated in breast and prostate cancers. In some cancer cells, PKB-alpha may act as a suppressor of metastasis. PKB contains an N-terminal pleckstrin homology (PH) domain and a C-terminal catalytic domain. The PKB-alpha 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 1370451447 126 DNIGEEEMDASTTHHKRK-TMNDFDYLKLLGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVLKNTR 204
Cdd:cd05594     4 DNSGAEEMEVSLTKPKHKvTMNDFEYLKLLGKGTFGKVILVKEKATGRYYAMKILKKEVIVAKDEVAHTLTENRVLQNSR 83

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370451447 205 HPFLTSLKYSFQTKDRLCFVMEYVNGGELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGK-IVYRDLK 273
Cdd:cd05594    84 HPFLTALKYSFQTHDRLCFVMEYANGGELFFHLSRERVFSEDRARFYGAEIVSALDYLHSEKnVVYRDLK 153

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 1370451447 154 LGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEYVNGGEL 233
Cdd:cd05123     1 LGKGSFGKVLLVRKKDTGKLYAMKVLRKKEIIKRKEVEHTLNERNILERVNHPFIVKLHYAFQTEEKLYLVLDYVPGGEL 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1370451447 234 FFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05123    81 FSHLSKEGRFPEERARFYAAEIVLALEYLHSLGIIYRDLK 120

Catalytic domain of the Serine/Threonine Kinase, Protein Kinase C; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain. PKCs undergo three phosphorylations in order to take mature forms. In addition, classical PKCs depend on calcium, DAG (1,2-diacylglycerol), and in most cases, phosphatidylserine (PS) for activation. Novel PKCs are calcium-independent, but require DAG and PS for activity, while atypical PKCs only require PS. PKCs phosphorylate and modify the activities of a wide variety of cellular proteins including receptors, enzymes, cytoskeletal proteins, transcription factors, and other kinases. They play a central role in signal transduction pathways that regulate cell migration and polarity, proliferation, differentiation, and apoptosis. Also included in this subfamily are the PKC-like proteins, called PKNs. The PKC 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 1370451447 152 KLLGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVL-KNTRHPFLTSLKYSFQTKDRLCFVMEYVNG 230
Cdd:cd05570     1 KVLGKGSFGKVMLAERKKTDELYAIKVLKKEVIIEDDDVECTMTEKRVLaLANRHPFLTGLHACFQTEDRLYFVMEYVNG 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1370451447 231 GELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05570    81 GDLMFHIQRARRFTEERARFYAAEICLALQFLHERGIIYRDLK 123

Catalytic domain of the Serine/Threonine Kinase, Serum- and Glucocorticoid-induced Kinase 2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. SGK2 shows a more restricted distribution than SGK1 and is most abundantly expressed in epithelial tissues including kidney, liver, pancreas, and the choroid plexus of the brain. In vitro cellular assays show that SGK2 can stimulate the activity of ion channels, the glutamate transporter EEAT4, and the glutamate receptors, GluR6 and GLUR1. The SGK2 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 1370451447 152 KLLGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVL-KNTRHPFLTSLKYSFQTKDRLCFVMEYVNG 230
Cdd:cd05603     1 KVIGKGSFGKVLLAKRKCDGKFYAVKVLQKKTILKKKEQNHIMAERNVLlKNLKHPFLVGLHYSFQTSEKLYFVLDYVNG 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1370451447 231 GELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05603    81 GELFFHLQRERCFLEPRARFYAAEVASAIGYLHSLNIIYRDLK 123

Catalytic domain of the Protein Serine/Threonine Kinase, Serum- and Glucocorticoid-induced Kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. SGK1 is ubiquitously expressed and is under transcriptional control of numerous stimuli including cell stress (cell shrinkage), serum, hormones (gluco- and mineralocorticoids), gonadotropins, growth factors, interleukin-6, and other cytokines. It plays roles in sodium retention and potassium elimination in the kidney, nutrient transport, salt sensitivity, memory consolidation, and cardiac repolarization. A common SGK1 variant is associated with increased blood pressure and body weight. SGK1 may also contribute to tumor growth, neurodegeneration, fibrosing disease, and ischemia. The SGK1 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 1370451447 146 NDFDYLKLLGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVL-KNTRHPFLTSLKYSFQTKDRLCFV 224
Cdd:cd05602     7 SDFHFLKVIGKGSFGKVLLARHKSDEKFYAVKVLQKKAILKKKEEKHIMSERNVLlKNVKHPFLVGLHFSFQTTDKLYFV 86

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 1370451447 225 MEYVNGGELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05602    87 LDYINGGELFYHLQRERCFLEPRARFYAAEIASALGYLHSLNIVYRDLK 135

Catalytic domain of Phototropin-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Phototropins are blue-light receptors that control responses such as phototropism, stromatal opening, and chloroplast movement in order to optimize the photosynthetic efficiency of plants. They are light-activated STKs that contain an N-terminal photosensory domain and a C-terminal catalytic domain. The N-terminal domain contains two LOV (Light, Oxygen or Voltage) domains that binds FMN. Photoexcitation of the LOV domains results in autophosphorylation at multiple sites and activation of the catalytic domain. In addition to plant phototropins, included in this subfamily are predominantly uncharacterized fungal STKs whose catalytic domains resemble the phototropin kinase domain. One protein from Neurospora crassa is called nrc-2, which plays a role in growth and development by controlling entry into the conidiation program. The phototropin-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 1370451447 147 DFDYLKLLGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVME 226
Cdd:cd05574     2 HFKKIKLLGKGDVGRVYLVRLKGTGKLFAMKVLDKEEMIKRNKVKRVLTEREILATLDHPFLPTLYASFQTSTHLCFVMD 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 1370451447 227 YVNGGELFFHLSR--ERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05574    82 YCPGGELFRLLQKqpGKRLPEEVARFYAAEVLLALEYLHLLGFVYRDLK 130

Catalytic domain of the Serine/Threonine Kinase, Novel Protein Kinase C epsilon; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PKC-epsilon has been shown to behave as an oncoprotein. Its overexpression contributes to neoplastic transformation depending on the cell type. It contributes to oncogenesis by inducing disordered cell growth and inhibiting cell death. It also plays a role in tumor invasion and metastasis. PKC-epsilon has also been found to confer cardioprotection against ischemia and reperfusion-mediated damage. Other cellular functions include the regulation of gene expression, cell adhesion, and cell motility. PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain. nPKCs are calcium-independent, but require DAG (1,2-diacylglycerol) and phosphatidylserine (PS) for activity. The nPKC-epsilon 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 1370451447 152 KLLGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVLK-NTRHPFLTSLKYSFQTKDRLCFVMEYVNG 230
Cdd:cd05591     1 KVLGKGSFGKVMLAERKGTDEVYAIKVLKKDVILQDDDVDCTMTEKRILAlAAKHPFLTALHSCFQTKDRLFFVMEYVNG 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1370451447 231 GELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05591    81 GDLMFQIQRARKFDEPRARFYAAEVTLALMFLHRHGVIYRDLK 123

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370451447  148 FDYLKLLGKGTFGKVILVREKASGKYYAMKILKKEVIiaKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEY 227
Cdd:smart00220   1 YEILEKLGEGSFGKVYLARDKKTGKLVAIKVIKKKKI--KKDRERILREIKILKKLKHPNIVRLYDVFEDEDKLYLVMEY 78

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*.
gi 1370451447  228 VNGGELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:smart00220  79 CEGGDLFDLLKKRGRLSEDEARFYLRQILSALEYLHSKGIVHRDLK 124

Catalytic domain of the Serine/Threonine Kinase, 70 kDa ribosomal protein S6 kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. p70S6K (or S6K) contains only one catalytic kinase domain, unlike p90 ribosomal S6 kinases (RSKs). It acts as a downstream effector of the STK mTOR (mammalian Target of Rapamycin) and plays a role in the regulation of the translation machinery during protein synthesis. p70S6K also plays a pivotal role in regulating cell size and glucose homeostasis. Its targets include S6, the translation initiation factor eIF3, and the insulin receptor substrate IRS-1, among others. Mammals contain two isoforms of p70S6K, named S6K1 and S6K2 (or S6K-beta). The p70S6K 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 1370451447 151 LKLLGKGTFGKVILVREKA---SGKYYAMKILKKEVII--AKDeVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVM 225
Cdd:cd05584     1 LKVLGKGGYGKVFQVRKTTgsdKGKIFAMKVLKKASIVrnQKD-TAHTKAERNILEAVKHPFIVDLHYAFQTGGKLYLIL 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1370451447 226 EYVNGGELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05584    80 EYLSGGELFMHLEREGIFMEDTACFYLAEITLALGHLHSLGIIYRDLK 127

N-terminal catalytic domain of the Serine/Threonine Kinase, Mitogen and stress-activated kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MSKs contain an N-terminal kinase domain (NTD) from the AGC family and a C-terminal kinase domain (CTD) from the CAMK family. MSKs are activated by two major signaling cascades, the Ras-MAPK and p38 stress kinase pathways, in response to various stimuli such as growth factors, hormones, neurotransmitters, cellular stress, and pro-inflammatory cytokines. This triggers phosphorylation in the activation loop (A-loop) of the CTD of MSK. The active CTD phosphorylates the hydrophobic motif (HM) in the C-terminal extension of NTD, which facilitates the phosphorylation of the A-loop and activates the NTD, which in turn phosphorylates downstream targets. MSKs are predominantly nuclear proteins. They are widely expressed in many tissues including heart, brain, lung, liver, kidney, and pancreas. There are two isoforms of MSK, called MSK1 and MSK2. The MSK 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 1370451447 154 LGKGTFGKVILVRE---KASGKYYAMKILKKEVIIAKDEVA-HTLTESRVLKNTRH-PFLTSLKYSFQTKDRLCFVMEYV 228
Cdd:cd05583     2 LGTGAYGKVFLVRKvggHDAGKLYAMKVLKKATIVQKAKTAeHTMTERQVLEAVRQsPFLVTLHYAFQTDAKLHLILDYV 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1370451447 229 NGGELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05583    82 NGGELFTHLYQREHFTESEVRIYIGEIVLALEHLHKLGIIYRDIK 126

Catalytic domain of Rho-associated coiled-coil containing protein kinase (ROCK)- and Nuclear Dbf2-Related (NDR)-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 ROCK and ROCK-like proteins such as DMPK, MRCK, and CRIK, as well as NDR and NDR-like proteins such as LATS, CBK1 and Sid2p. ROCK and CRIK are effectors of the small GTPase Rho, while MRCK is an effector of the small GTPase Cdc42. NDR and NDR-like kinases contain an N-terminal regulatory (NTR) domain and an insert within the catalytic domain that contains an auto-inhibitory sequence. Proteins in this subfamily are involved in regulating many cellular functions including contraction, motility, division, proliferation, apoptosis, morphogenesis, and cytokinesis. The ROCK/NDR-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 1370451447 146 NDFDYLKLLGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVM 225
Cdd:cd05573     1 DDFEVIKVIGRGAFGEVWLVRDKDTGQVYAMKILRKSDMLKREQIAHVRAERDILADADSPWIVRLHYAFQDEDHLYLVM 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1370451447 226 EYVNGGELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05573    81 EYMPGGDLMNLLIKYDVFPEETARFYIAELVLALDSLHKLGFIHRDIK 128

Catalytic domain of Suppressor of loss of cAMP-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 Schizosaccharomyces pombe Sck1 and similar fungal proteins. Sck1 plays a role in trehalase activation triggered by glucose and a nitrogen source. Trehalase catalyzes the cleavage of the disaccharide trehalose to glucose. Trehalose, as a carbohydrate reserve and stress metabolite, plays an important role in the response of yeast to environmental changes. The Sck1-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 1370451447 154 LGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVLKNT---RHPFLTSLKYSFQTKDRLCFVMEYVNG 230
Cdd:cd05586     1 IGKGTFGQVYQVRKKDTRRIYAMKVLSKKVIVAKKEVAHTIGERNILVRTaldESPFIVGLKFSFQTPTDLYLVTDYMSG 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1370451447 231 GELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05586    81 GELFWHLQKEGRFSEDRAKFYIAELVLALEHLHKNDIVYRDLK 123

Catalytic domain of the Serine/Threonine Kinase, Phosphoinositide-dependent kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PDK1 carries an N-terminal catalytic domain and a C-terminal pleckstrin homology (PH) domain that binds phosphoinositides. It phosphorylates the activation loop of AGC kinases that are regulated by PI3K such as PKB, SGK, and PKC, among others, and is crucial for their activation. Thus, it contributes in regulating many processes including metabolism, growth, proliferation, and survival. PDK1 also has the ability to autophosphorylate and is constitutively active in mammalian cells. It is essential for normal embryo development and is important in regulating cell volume. The PDK1 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370451447 146 NDFDYLKLLGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVM 225
Cdd:cd05581     1 NDFKFGKPLGEGSYSTVVLAKEKETGKEYAIKVLDKRHIIKEKKVKYVTIEKEVLSRLAHPGIVKLYYTFQDESKLYFVL 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1370451447 226 EYVNGGELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05581    81 EYAPNGDLLEYIRKYGSLDEKCTRFYTAEIVLALEYLHSKGIIHRDLK 128

Catalytic domain of Yeast Protein Kinase 1-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 fungal proteins with similarity to the AGC STKs, Saccharomyces cerevisiae YPK1 and Schizosaccharomyces pombe Gad8p. YPK1 is required for cell growth and acts as a downstream kinase in the sphingolipid-mediated signaling pathway of yeast. It also plays a role in efficient endocytosis and in the maintenance of cell wall integrity. Gad8p is a downstream target of Tor1p, the fission yeast homolog of mTOR. It plays a role in cell growth and sexual development. The YPK1-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 1370451447 153 LLGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEYVNGGE 232
Cdd:cd05585     1 VIGKGSFGKVMQVRKKDTSRIYALKTIRKAHIVSRSEVTHTLAERTVLAQVDCPFIVPLKFSFQSPEKLYLVLAFINGGE 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1370451447 233 LFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05585    81 LFHHLQREGRFDLSRARFYTAELLCALECLHKFNVIYRDLK 121

Catalytic domain of the Serine/Threonine Kinase, Novel Protein Kinase C theta; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PKC-theta is selectively expressed in T-cells and plays an important and non-redundant role in several aspects of T-cell biology. Although T-cells also express other PKC isoforms, PKC-theta is unique in that upon antigen stimulation, it is translocated to the plasma membrane at the immunological synapse, where it mediates signals essential for T-cell activation. It is essential for TCR-induced proliferation, cytokine production, T-cell survival, and the differentiation and effector function of T-helper (Th) cells, particularly Th2 and Th17. PKC-theta is being developed as a therapeutic target for Th2-mediated allergic inflammation and Th17-mediated autoimmune diseases. PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain. nPKCs are calcium-independent, but require DAG (1,2-diacylglycerol) and phosphatidylserine (PS) for activity. The nPKC 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 1370451447 144 TMNDFDYLKLLGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVLKNT-RHPFLTSLKYSFQTKDRLC 222
Cdd:cd05619     3 TIEDFVLHKMLGKGSFGKVFLAELKGTNQFFAIKALKKDVVLMDDDVECTMVEKRVLSLAwEHPFLTHLFCTFQTKENLF 82

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1370451447 223 FVMEYVNGGELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05619    83 FVMEYLNGGDLMFHIQSCHKFDLPRATFYAAEIICGLQFLHSKGIVYRDLK 133

N-terminal catalytic domain of the Serine/Threonine Kinase, Mitogen and stress-activated kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MSK1 plays a role in the regulation of translational control and transcriptional activation. It phosphorylates the transcription factors, CREB and NFkB. It also phosphorylates the nucleosomal proteins H3 and HMG-14. Increased phosphorylation of MSK1 is associated with the development of cerebral ischemic/hypoxic preconditioning. MSKs contain an N-terminal kinase domain (NTD) from the AGC family and a C-terminal kinase domain (CTD) from the CAMK family. MSKs are activated by two major signaling cascades, the Ras-MAPK and p38 stress kinase pathways, which trigger phosphorylation in the activation loop (A-loop) of the CTD of MSK. The active CTD phosphorylates the hydrophobic motif (HM) of NTD, which facilitates the phosphorylation of the A-loop and activates the NTD, which in turn phosphorylates downstream targets. The MSK1 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 1370451447 147 DFDYLKLLGKGTFGKVILVREKA---SGKYYAMKILKKEVIIAKDEVA-HTLTESRVLKNTRH-PFLTSLKYSFQTKDRL 221
Cdd:cd05613     1 NFELLKVLGTGAYGKVFLVRKVSghdAGKLYAMKVLKKATIVQKAKTAeHTRTERQVLEHIRQsPFLVTLHYAFQTDTKL 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1370451447 222 CFVMEYVNGGELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05613    81 HLILDYINGGELFTHLSQRERFTENEVQIYIGEIVLALEHLHKLGIIYRDIK 132

Catalytic domain of the Serine/Threonine Kinase, Classical Protein Kinase C alpha; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PKC-alpha is expressed in many tissues and is associated with cell proliferation, apoptosis, and cell motility. It plays a role in the signaling of the growth factors PDGF, VEGF, EGF, and FGF. Abnormal levels of PKC-alpha have been detected in many transformed cell lines and several human tumors. In addition, PKC-alpha is required for HER2 dependent breast cancer invasion. PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain. PKCs undergo three phosphorylations in order to take mature forms. In addition, cPKCs depend on calcium, DAG (1,2-diacylglycerol), and in most cases, phosphatidylserine (PS) for activation. The cPKC-alpha subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370451447 145 MNDFDYLKLLGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEVAHTLTESRVL-KNTRHPFLTSLKYSFQTKDRLCF 223
Cdd:cd05615     9 LTDFNFLMVLGKGSFGKVMLAERKGSDELYAIKILKKDVVIQDDDVECTMVEKRVLaLQDKPPFLTQLHSCFQTVDRLYF 88

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 1370451447 224 VMEYVNGGELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05615    89 VMEYVNGGDLMYHIQQVGKFKEPQAVFYAAEISVGLFFLHKKGIIYRDLK 138

N-terminal catalytic domain of the Serine/Threonine Kinase, 90 kDa ribosomal protein S6 kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. RSKs contain an N-terminal kinase domain (NTD) from the AGC family and a C-terminal kinase domain (CTD) from the CAMK family. They are activated by signaling inputs from extracellular regulated kinase (ERK) and phosphoinositide dependent kinase 1 (PDK1). ERK phosphorylates and activates the CTD of RSK, serving as a docking site for PDK1, which phosphorylates and activates the NTD, which in turn phosphorylates all known RSK substrates. RSKs act as downstream effectors of mitogen-activated protein kinase (MAPK) and play key roles in mitogen-activated cell growth, differentiation, and survival. Mammals possess four RSK isoforms (RSK1-4) from distinct genes. RSK proteins are also referred to as MAP kinase-activated protein kinases (MAPKAPKs), p90-RSKs, or p90S6Ks. The RSK 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 1370451447 152 KLLGKGTFGKVILVRE---KASGKYYAMKILKKEVIIAKDEVaHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEYV 228
Cdd:cd05582     1 KVLGQGSFGKVFLVRKitgPDAGTLYAMKVLKKATLKVRDRV-RTKMERDILADVNHPFIVKLHYAFQTEGKLYLILDFL 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1370451447 229 NGGELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05582    80 RGGDLFTRLSKEVMFTEEDVKFYLAELALALDHLHSLGIIYRDLK 124

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 1370451447 147 DFDYLKLLGKGTFGKVILVREKASGKYYAMKILKKEVIIAKDEvAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVME 226
Cdd:cd05117     1 KYELGKVLGRGSFGVVRLAVHKKTGEEYAVKIIDKKKLKSEDE-EMLRREIEILKRLDHPNIVKLYEVFEDDKNLYLVME 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1370451447 227 YVNGGELFFHLSRERVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLK 273
Cdd:cd05117    80 LCTGGELFDRIVKKGSFSEREAAKIMKQILSAVAYLHSQGIVHRDLK 126