Serine/threonine protein kinase [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 116283318  19 RYLFVQKLGEGGFSYVDLVEGLHDGHFYALKRILCHEQQDQEEAQR---EAEMHRLFQHPNILRLMAYSlKERGakhEAW 95
Cdd:COG0515    8 RYRILRLLGRGGMGVVYLARDLRLGRPVALKVLRPELAADPEARERfrrEARALARLNHPNIVRVYDVG-EEDG---RPY 83

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 116283318  96 LLLPFFKKGTLWneiERLKDQGSfLTEDQILPLLLGISRGLEAIHAKGYAHRDLKPTNILLGDEGQPVLMDLG 168
Cdd:COG0515   84 LVMEYVEGESLA---DLLRRRGP-LPPAEALRILAQLAEALAAAHAAGIVHRDIKPANILLTPDGRVKLIDFG 152

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 116283318   22 FVQKLGEGGFSYVdlVEG----LHDGHFY--ALKRILC-HEQQDQEEAQREAEMHRLFQHPNILRLMAYSLKERgakhEA 94
Cdd:pfam07714   3 LGEKLGEGAFGEV--YKGtlkgEGENTKIkvAVKTLKEgADEEEREDFLEEASIMKKLDHPNIVKLLGVCTQGE----PL 76

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 116283318   95 WLLLPFFKKGTLWNeieRLKDQGSFLTEDQILPLLLGISRGLEAIHAKGYAHRDLKPTNILLGDEGQ 161
Cdd:pfam07714  77 YIVTEYMPGGDLLD---FLRKHKRKLTLKDLLSMALQIAKGMEYLESKNFVHRDLAARNCLVSENLV 140

Stk1 family PASTA domain-containing Ser/Thr kinase;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 116283318  14 IIDNkRYLFVQKLGEGGFSYVDLVEGLHDGHFYALKRI---LCHEQQDQEEAQREAE-MHRLfQHPNILRL--------- 80
Cdd:NF033483   4 LLGG-RYEIGERIGRGGMAEVYLAKDTRLDRDVAVKVLrpdLARDPEFVARFRREAQsAASL-SHPNIVSVydvgedggi 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 116283318  81 ----MAY----SLKERgakheawlllpffkkgtlwneierLKDQGSfLTEDQILPLLLGISRGLEAIHAKGYAHRDLKPT 152
Cdd:NF033483  82 pyivMEYvdgrTLKDY------------------------IREHGP-LSPEEAVEIMIQILSALEHAHRNGIVHRDIKPQ 136

                        170
                 ....*....|....*.
gi 116283318 153 NILLGDEGQPVLMDLG 168
Cdd:NF033483 137 NILITKDGRVKVTDFG 152

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 116283318  26 LGEGGFSYVDLVEGLHDGHFYALKRI-LCHEQQDQEEAQREAEMHRLFQHPNILRLMAYSLKERgakhEAWLLLPFFKKG 104
Cdd:cd00180    1 LGKGSFGKVYKARDKETGKKVAVKVIpKEKLKKLLEELLREIEILKKLNHPNIVKLYDVFETEN----FLYLVMEYCEGG 76

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 116283318 105 TLWNEIERLKDQgsfLTEDQILPLLLGISRGLEAIHAKGYAHRDLKPTNILLGDEGQPVLMDLGSMNQACIQVEGSRQAL 184
Cdd:cd00180   77 SLKDLLKENKGP---LSEEEALSILRQLLSALEYLHSNGIIHRDLKPENILLDSDGTVKLADFGLAKDLDSDDSLLKTTG 153

                 ....*....
gi 116283318 185 ALQLWGHCS 193
Cdd:cd00180  154 GTTPPYYAP 162

Catalytic domain of bacterial Serine/Threonine kinases, PknB and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily includes many bacterial eukaryotic-type STKs including Staphylococcus aureus PknB (also called PrkC or Stk1), Bacillus subtilis PrkC, and Mycobacterium tuberculosis Pkn proteins (PknB, PknD, PknE, PknF, PknL, and PknH), among others. S. aureus PknB is the only eukaryotic-type STK present in this species, although many microorganisms encode for several such proteins. It is important for the survival and pathogenesis of S. aureus as it is involved in the regulation of purine and pyrimidine biosynthesis, cell wall metabolism, autolysis, virulence, and antibiotic resistance. M. tuberculosis PknB is essential for growth and it acts on diverse substrates including proteins involved in peptidoglycan synthesis, cell division, transcription, stress responses, and metabolic regulation. B. subtilis PrkC is located at the inner membrane of endospores and functions to trigger spore germination. Bacterial STKs in this subfamily show varied domain architectures. The well-characterized members such as S. aureus and M. tuberculosis PknB, and B. subtilis PrkC, contain an N-terminal cytosolic kinase domain, a transmembrane (TM) segment, and mutliple C-terminal extracellular PASTA domains. The PknB 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 116283318  19 RYLFVQKLGEGGFSYVDLVEGLHDGHFYALKRILCHEQQDQEE---AQREAEMHRLFQHPNILRLMAYSLKERGAkheaW 95
Cdd:cd14014    1 RYRLVRLLGRGGMGEVYRARDTLLGRPVAIKVLRPELAEDEEFrerFLREARALARLSHPNIVRVYDVGEDDGRP----Y 76

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 116283318  96 LLLPFFKKGTLwneIERLKDQGSfLTEDQILPLLLGISRGLEAIHAKGYAHRDLKPTNILLGDEGQPVLMDLG 168
Cdd:cd14014   77 IVMEYVEGGSL---ADLLRERGP-LPPREALRILAQIADALAAAHRAGIVHRDIKPANILLTEDGRVKLTDFG 145

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 116283318    20 YLFVQKLGEGGFSYVDLVEGLHDGHFYALKRI-LCHEQQDQEEAQREAEMHRLFQHPNILRLMaYSLKErgaKHEAWLLL 98
Cdd:smart00220   1 YEILEKLGEGSFGKVYLARDKKTGKLVAIKVIkKKKIKKDRERILREIKILKKLKHPNIVRLY-DVFED---EDKLYLVM 76

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 116283318    99 PFFKKGTLWneiERLKDQGSFlTEDQILPLLLGISRGLEAIHAKGYAHRDLKPTNILLGDEGQPVLMDLGS 169
Cdd:smart00220  77 EYCEGGDLF---DLLKKRGRL-SEDEARFYLRQILSALEYLHSKGIVHRDLKPENILLDEDGHVKLADFGL 143

Catalytic domain of STE family Protein Kinases; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine (ST) or tyrosine residues on protein substrates. This family is composed of STKs, and some dual-specificity PKs that phosphorylate both threonine and tyrosine residues of target proteins. Most members are kinases involved in mitogen-activated protein kinase (MAPK) signaling cascades, acting as MAPK kinases (MAPKKs), MAPKK kinases (MAPKKKs), or MAPKKK kinases (MAP4Ks). The MAPK signaling pathways are important mediators of cellular responses to extracellular signals. The pathways involve a triple kinase core cascade comprising of the MAPK, which is phosphorylated and activated by a MAPKK, which itself is phosphorylated and activated by a MAPKKK. Each MAPK cascade is activated either by a small GTP-binding protein or by an adaptor protein, which transmits the signal either directly to a MAPKKK to start the triple kinase core cascade or indirectly through a mediator kinase, a MAP4K. Other STE family members include p21-activated kinases (PAKs) and class III myosins, among others. PAKs are Rho family GTPase-regulated kinases that serve as important mediators in the function of Cdc42 (cell division cycle 42) and Rac. Class III myosins are motor proteins containing an N-terminal kinase catalytic domain and a C-terminal actin-binding domain, which can phosphorylate several cytoskeletal proteins, conventional myosin regulatory light chains, as well as autophosphorylate the C-terminal motor domain. They play an important role in maintaining the structural integrity of photoreceptor cell microvilli. The STE 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 116283318  20 YLFVQKLGEGGFSYVDLVEGLHDGHFYALKRILCHEQQDQEEAQREAEMHRLFQHPNILRLMAYSLKergaKHEAWLLLP 99
Cdd:cd05122    2 FEILEKIGKGGFGVVYKARHKKTGQIVAIKKINLESKEKKESILNEIAILKKCKHPNIVKYYGSYLK----KDELWIVME 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 116283318 100 FFKKGTLwNEIERLKDQGsfLTEDQILPLLLGISRGLEAIHAKGYAHRDLKPTNILLGDEGQPVLMDLGsmnqACIQVEG 179
Cdd:cd05122   78 FCSGGSL-KDLLKNTNKT--LTEQQIAYVCKEVLKGLEYLHSHGIIHRDIKAANILLTSDGEVKLIDFG----LSAQLSD 150

                 ...
gi 116283318 180 SRQ 182
Cdd:cd05122  151 GKT 153

Catalytic domain of the Serine/Threonine Kinases, Chlamydomonas reinhardtii CNK2 and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Chlamydomonas reinhardtii CNK2 has both cilliary and cell cycle functions. It influences flagellar length through promoting flagellar disassembly, and it regulates cell size, through influencing the size threshold at which cells commit to mitosis. This subfamily belongs to the (NIMA)-related kinase (Nek) family, which includes seven different Chlamydomonas Neks (CNKs 1-6 and Fa2). This subfamily includes CNK1, and -2. 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 116283318  25 KLGEGGFSYVDLVEGLHDGHFYALKRIlchEQQDQEEAQREAEMH--RL---FQHPNILRLmayslkergakHEAWLL-- 97
Cdd:cd08530    7 KLGKGSYGSVYKVKRLSDNQVYALKEV---NLGSLSQKEREDSVNeiRLlasVNHPNIIRY-----------KEAFLDgn 72

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 116283318  98 -----LPFFKKGTLWNEIERLKDQGSFLTEDQILPLLLGISRGLEAIHAKGYAHRDLKPTNILLGDEGQPVLMDLG 168
Cdd:cd08530   73 rlcivMEYAPFGDLSKLISKRKKKRRLFPEDDIWRIFIQMLRGLKALHDQKILHRDLKSANILLSAGDLVKIGDLG 148

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 116283318  20 YLFVQKLGEGGFSYVDLVEGLHDGHFYALKRILCHEQqDQEEAQREAEMHRLF----QHPNILRLMaYSLKERGAKHeAW 95
Cdd:cd05118    1 YEVLRKIGEGAFGTVWLARDKVTGEKVAIKKIKNDFR-HPKAALREIKLLKHLndveGHPNIVKLL-DVFEHRGGNH-LC 77

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 116283318  96 LLLPFFkkGTLWNEIerLKDQGSFLTEDQILPLLLGISRGLEAIHAKGYAHRDLKPTNILL-GDEGQPVLMDLGS 169
Cdd:cd05118   78 LVFELM--GMNLYEL--IKDYPRGLPLDLIKSYLYQLLQALDFLHSNGIIHRDLKPENILInLELGQLKLADFGL 148

Catalytic domain of the Serine/Threonine kinase, Aurora kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Aurora kinases are key regulators of mitosis and are essential for the accurate and equal division of genomic material from parent to daughter cells. Yeast contains only one Aurora kinase while most higher eukaryotes have two. Vertebrates contain at least 2 Aurora kinases (A and B); mammals contains a third Aurora kinase gene (C). Aurora-A regulates cell cycle events from the late S-phase through the M-phase including centrosome maturation, mitotic entry, centrosome separation, spindle assembly, chromosome alignment, cytokinesis, and mitotic exit. Aurora-A activation depends on its autophosphorylation and binding to the microtubule-associated protein TPX2. Aurora-B is most active at the transition during metaphase to the end of mitosis. It is critical for accurate chromosomal segregation, cytokinesis, protein localization to the centrosome and kinetochore, correct microtubule-kinetochore attachments, and regulation of the mitotic checkpoint. Aurora-C is mainly expressed in meiotically dividing cells; it was originally discovered in mice as a testis-specific STK called Aie1. Both Aurora-B and -C are chromosomal passenger proteins that can form complexes with INCENP and survivin, and they may have redundant cellular functions. The Aurora 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 116283318  22 FVQKLGEGGFSYVDLVEGLHDGHFYALK-----RILCHEQQDQeeAQREAEMHRLFQHPNILRLMAYSlkergakHEA-- 94
Cdd:cd14007    4 IGKPLGKGKFGNVYLAREKKSGFIVALKvisksQLQKSGLEHQ--LRREIEIQSHLRHPNILRLYGYF-------EDKkr 74

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 116283318  95 -WLLLPFFKKGTLWNEierLKDQGSFlTEDQILPLLLGISRGLEAIHAKGYAHRDLKPTNILLGDEGQPVLMDLG 168
Cdd:cd14007   75 iYLILEYAPNGELYKE---LKKQKRF-DEKEAAKYIYQLALALDYLHSKNIIHRDIKPENILLGSNGELKLADFG 145

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 116283318  26 LGEGGFSyvDLVEGLHDGHFYALKRILCHEQQDQ--EEAQREAEMHRLFQHPNILRLMAYSLKERgakhEAWLLLPFFKK 103
Cdd:cd13999    1 IGSGSFG--EVYKGKWRGTDVAIKKLKVEDDNDEllKEFRREVSILSKLRHPNIVQFIGACLSPP----PLCIVTEYMPG 74

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 116283318 104 GTLWNeieRLKDQGSFLTEDQILPLLLGISRGLEAIHAKGYAHRDLKPTNILLGDEGQPVLMDLG 168
Cdd:cd13999   75 GSLYD---LLHKKKIPLSWSLRLKIALDIARGMNYLHSPPIIHRDLKSLNILLDENFTVKIADFG 136

Catalytic domain of the Serine/Threonine protein kinase, cyclin G-Associated Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. GAK, also called auxilin-2, contains an N-terminal kinase domain that phosphorylates the mu subunits of adaptor protein (AP) 1 and AP2. In addition, it contains an auxilin-1-like domain structure consisting of PTEN-like, clathrin-binding, and J domains. Like auxilin-1, GAK facilitates Hsc70-mediated dissociation of clathrin from clathrin-coated vesicles. GAK is expressed ubiquitously and is enriched in the Golgi, unlike auxilin-1 which is nerve-specific. GAK also plays regulatory roles outside of clathrin-mediated membrane traffic including the maintenance of centrosome integrity and chromosome congression, neural patterning, survival of neurons, and immune responses through interaction with the interleukin 12 receptor. It also interacts with the androgen receptor, acting as a transcriptional coactivator, and its expression is significantly increased with the progression of prostate cancer. The GAK 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 116283318  26 LGEGGFSYVDLVEGLHDGHFYALKRILCHEQQDQEEAQREAEMH-RLFQHPNILRLMA---YSLKERGAKHEAWLLLPFF 101
Cdd:cd14036    8 IAEGGFAFVYEAQDVGTGKEYALKRLLSNEEEKNKAIIQEINFMkKLSGHPNIVQFCSaasIGKEESDQGQAEYLLLTEL 87

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 116283318 102 KKGTLWNEIERLKDQGSFlTEDQILPLLLGISRGLEAIHAKG--YAHRDLKPTNILLGDEGQPVLMDLGS 169
Cdd:cd14036   88 CKGQLVDFVKKVEAPGPF-SPDTVLKIFYQTCRAVQHMHKQSppIIHRDLKIENLLIGNQGQIKLCDFGS 156

The catalytic domain of the Serine/Threonine Kinase, Glycogen Synthase Kinase 3; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. GSK3 is a mutifunctional kinase involved in many cellular processes including cell division, proliferation, differentiation, adhesion, and apoptosis. In plants, GSK3 plays a role in the response to osmotic stress. In Caenorhabditis elegans, it plays a role in regulating normal oocyte-to-embryo transition and response to oxidative stress. In Chlamydomonas reinhardtii, GSK3 regulates flagellar length and assembly. In mammals, there are two isoforms, GSK3alpha and GSK3beta, which show both distinct and redundant functions. The two isoforms differ mainly in their N-termini. They are both involved in axon formation and in Wnt signaling.They play distinct roles in cardiogenesis, with GSKalpha being essential in cardiomyocyte survival, and GSKbeta regulating heart positioning and left-right symmetry. GSK3beta was first identified as a regulator of glycogen synthesis, but has since been determined to play other roles. It regulates the degradation of beta-catenin and IkB. Beta-catenin is the main effector of Wnt, which is involved in normal haematopoiesis and stem cell function. IkB is a central inhibitor of NF-kB, which is critical in maintaining leukemic cell growth. GSK3beta is enriched in the brain and is involved in regulating neuronal signaling pathways. It is implicated in the pathogenesis of many diseases including Type II diabetes, obesity, mood disorders, Alzheimer's disease, osteoporosis, and some types of cancer, among others. The GSK3 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 116283318  17 NKRYLFVQKLGEGGFSYVDLVEGLHDGHFYALKRILcheqQDQEEAQREAEMHRLFQHPNILRLMAYSLKERGAKHEAWL 96
Cdd:cd14137    3 EISYTIEKVIGSGSFGVVYQAKLLETGEVVAIKKVL----QDKRYKNRELQIMRRLKHPNIVKLKYFFYSSGEKKDEVYL 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 116283318  97 LLPF-FKKGTLWNEIERLKDQGsfltedQILPLLL------GISRGLEAIHAKGYAHRDLKPTNILLGDE-GQPVLMDLG 168
Cdd:cd14137   79 NLVMeYMPETLYRVIRHYSKNK------QTIPIIYvklysyQLFRGLAYLHSLGICHRDIKPQNLLVDPEtGVLKLCDFG 152

                 .
gi 116283318 169 S 169
Cdd:cd14137  153 S 153

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 116283318  19 RYLFVQKLGEGGFSYVDLVEGLHDGHFYALKRILCHEQQD--QEEAQREAEMHRLFQHPNILRL--MAY--SLKERGAKH 92
Cdd:cd07866    9 DYEILGKLGEGTFGEVYKARQIKTGRVVALKKILMHNEKDgfPITALREIKILKKLKHPNVVPLidMAVerPDKSKRKRG 88

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 116283318  93 EAWLLLPFFKK---GTLWNEieRLKdqgsfLTEDQILPLLLGISRGLEAIHAKGYAHRDLKPTNILLGDEGQPVLMDLG 168
Cdd:cd07866   89 SVYMVTPYMDHdlsGLLENP--SVK-----LTESQIKCYMLQLLEGINYLHENHILHRDIKAANILIDNQGILKIADFG 160

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 116283318  19 RYLFVQKLGEGGFSYVDLVEGLHDGHFYALKrILCHEQQDQEEA---QREAEMHRLFQHPNILRLmaYSLKERGAKHeaW 95
Cdd:cd14003    1 NYELGKTLGEGSFGKVKLARHKLTGEKVAIK-IIDKSKLKEEIEekiKREIEIMKLLNHPNIIKL--YEVIETENKI--Y 75

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 116283318  96 LLLPFFKKGTLwneIERLKDQGSfLTEDQILPLLLGISRGLEAIHAKGYAHRDLKPTNILLGDEGQPVLMDLG 168
Cdd:cd14003   76 LVMEYASGGEL---FDYIVNNGR-LSEDEARRFFQQLISAVDYCHSNGIVHRDLKLENILLDKNGNLKIIDFG 144

Catalytic domain of the Serine/Threonine Kinase, Cyclin-Dependent protein Kinase 7; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CDK7 plays essential roles in the cell cycle and in transcription. It associates with cyclin H and MAT1 and acts as a CDK-Activating Kinase (CAK) by phosphorylating and activating cell cycle CDKs (CDK1/2/4/6). In the brain, it activates CDK5. CDK7 is also a component of the general transcription factor TFIIH, which phosphorylates the C-terminal domain (CTD) of RNA polymerase II when it is bound with unphosphorylated DNA, as present in the pre-initiation complex. Following phosphorylation, the CTD dissociates from the DNA which allows transcription initiation. 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 CDK7 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 116283318  19 RYLFVQKLGEGGFSYVDLVEGLHDGHFYALKRI-LCHEQQDQE----EAQREAEMHRLFQHPNILRLM-AYslkerGAKH 92
Cdd:cd07841    1 RYEKGKKLGEGTYAVVYKARDKETGRIVAIKKIkLGERKEAKDginfTALREIKLLQELKHPNIIGLLdVF-----GHKS 75

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 116283318  93 EAWLLLPFfkkgtLWNEIERL-KDQGSFLTEDQILPLLLGISRGLEAIHAKGYAHRDLKPTNILLGDEGQPVLMDLG 168
Cdd:cd07841   76 NINLVFEF-----METDLEKViKDKSIVLTPADIKSYMLMTLRGLEYLHSNWILHRDLKPNNLLIASDGVLKLADFG 147

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 116283318  26 LGEGGFSYVDLVEGLHDGHFYALKRI----LCHEQQDQEEA----------QRE-AEMHRLfQHPNILRLmayslkerga 90
Cdd:cd14008    1 LGRGSFGKVKLALDTETGQLYAIKIFnksrLRKRREGKNDRgkiknalddvRREiAIMKKL-DHPNIVRL---------- 69

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 116283318  91 kHEA---------WLLLPFFKKGTLwneIERLKDQGSF-LTEDQILPLLLGISRGLEAIHAKGYAHRDLKPTNILLGDEG 160
Cdd:cd14008   70 -YEViddpesdklYLVLEYCEGGPV---MELDSGDRVPpLPEETARKYFRDLVLGLEYLHENGIVHRDIKPENLLLTADG 145

                 ....*....
gi 116283318 161 QPVLMDLGS 169
Cdd:cd14008  146 TVKISDFGV 154

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 116283318   22 FVQKLGEGGFSYVdlVEG----LHDGHFY--ALKRILC-HEQQDQEEAQREAEMHRLFQHPNILRLMAYSLKERgakhEA 94
Cdd:pfam07714   3 LGEKLGEGAFGEV--YKGtlkgEGENTKIkvAVKTLKEgADEEEREDFLEEASIMKKLDHPNIVKLLGVCTQGE----PL 76

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 116283318   95 WLLLPFFKKGTLWNeieRLKDQGSFLTEDQILPLLLGISRGLEAIHAKGYAHRDLKPTNILLGDEGQ 161
Cdd:pfam07714  77 YIVTEYMPGGDLLD---FLRKHKRKLTLKDLLSMALQIAKGMEYLESKNFVHRDLAARNCLVSENLV 140

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 116283318  20 YLFVQKLGEGGFSYVDLVEGLHDGHFYALK---RILCHEQQDQEEAQREAE-MHRLfQHPNILRLmAYSLKERgakHEAW 95
Cdd:cd05581    3 FKFGKPLGEGSYSTVVLAKEKETGKEYAIKvldKRHIIKEKKVKYVTIEKEvLSRL-AHPGIVKL-YYTFQDE---SKLY 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 116283318  96 LLLPFFKKGTLWNEIERLkdqGSFLTED------QILplllgisRGLEAIHAKGYAHRDLKPTNILLGDEGQPVLMDLGS 169
Cdd:cd05581   78 FVLEYAPNGDLLEYIRKY---GSLDEKCtrfytaEIV-------LALEYLHSKGIIHRDLKPENILLDEDMHIKITDFGT 147

Catalytic domain of the Protein Serine/Threonine Kinase, Never In Mitosis gene A (NIMA)-related kinase 11; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Nek11 is involved, through direct phosphorylation, in regulating the degradation of Cdc25A (Cell Division Cycle 25 homolog A), which plays a role in cell cycle progression and in activating cyclin dependent kinases. Nek11 is activated by CHK1 (CHeckpoint Kinase 1) and may be involved in the G2/M checkpoint. Nek11 may also play a role in the S-phase checkpoint as well as in DNA replication and genotoxic stress responses. It is one in a family of 11 different Neks (Nek1-11) that are involved in cell cycle control. 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.