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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1371546634 320 NGNIVLISEFF--------------GENVFDYIKRKKNtlfvvsdISNEDKKKILYNSLNLLMRLHNAGLTHLDLSPDNM 385
Cdd:cd14174    59 NKNILELIEFFeddtrfylvfeklrGGSILAHIQKRKH-------FNEREASRVVRDIASALDFLHTKGIAHRDLKPENI 131

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1371546634 386 L------ISPknyeMRLCDLSQSTPIytnklrhkeKLNS----IKPFESFEPCiGKIEYIPPECWKIVwkykmnniknpi 455
Cdd:cd14174   132 LcespdkVSP----VKICDFDLGSGV---------KLNSactpITTPELTTPC-GSAEYMAPEVVEVF------------ 185

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1371546634 456 eylknisnqeERKKYYYDVSCaDKYMLGIFFIWM----------------WNNGFIWKCSdpiQDKIFEIFMKSNMDLNK 519
Cdd:cd14174   186 ----------TDEATFYDKRC-DLWSLGVILYIMlsgyppfvghcgtdcgWDRGEVCRVC---QNKLFESIQEGKYEFPD 251

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|
gi 1371546634 520 fimtKSWPH---ELNNLINKLLHMEHRKTVKLSDLSRHPW 556
Cdd:cd14174   252 ----KDWSHissEAKDLISKLLVRDAKERLSAAQVLQHPW 287

Catalytic domain of the Serine/Threonine kinase, Mitogen-activated protein kinase signal-integrating kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MAPK signal-integrating kinases (Mnks) are MAPK-activated protein kinases and is comprised by a group of four proteins, produced by alternative splicing from two genes (Mnk1 and Mnk2). The isoforms of Mnk1 (1a/1b) and Mnk2 (2a/2b) differ at their C-termini, with the a-form having a longer C-terminus containing a MAPK-binding region. All Mnks contain a catalytic kinase domain and a polybasic region at the N-terminus which binds importin and the eukaryotic initiation factor eIF4G. The best characterized Mnk substrate is eIF4G, whose phosphorylation may promote the export of certain mRNAs from the nucleus. Mnk also phosphorylate substrates that bind to AU-rich elements that regulate mRNA stability and translation. Mnks have also been implicated in tyrosine kinase receptor signaling, inflammation, and cell prolieration or survival. The Mnk 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 1371546634 320 NGNIVLISEFF--------------GENVFDYIKRKKNtlfvvsdISNEDKKKILYNSLNLLMRLHNAGLTHLDLSPDNM 385
Cdd:cd14174    59 NKNILELIEFFeddtrfylvfeklrGGSILAHIQKRKH-------FNEREASRVVRDIASALDFLHTKGIAHRDLKPENI 131

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1371546634 386 L------ISPknyeMRLCDLSQSTPIytnklrhkeKLNS----IKPFESFEPCiGKIEYIPPECWKIVwkykmnniknpi 455
Cdd:cd14174   132 LcespdkVSP----VKICDFDLGSGV---------KLNSactpITTPELTTPC-GSAEYMAPEVVEVF------------ 185

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1371546634 456 eylknisnqeERKKYYYDVSCaDKYMLGIFFIWM----------------WNNGFIWKCSdpiQDKIFEIFMKSNMDLNK 519
Cdd:cd14174   186 ----------TDEATFYDKRC-DLWSLGVILYIMlsgyppfvghcgtdcgWDRGEVCRVC---QNKLFESIQEGKYEFPD 251

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|
gi 1371546634 520 fimtKSWPH---ELNNLINKLLHMEHRKTVKLSDLSRHPW 556
Cdd:cd14174   252 ----KDWSHissEAKDLISKLLVRDAKERLSAAQVLQHPW 287

glycogen synthase kinase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1371546634 294 KNCKKYKFQDLNELNDILTK---------KLENNINGNIVLisEFFGENVFDYIK---RKKNTL--FVVSDISnedkkki 359
Cdd:PTZ00036  106 KNRELLIMKNLNHINIIFLKdyyytecfkKNEKNIFLNVVM--EFIPQTVHKYMKhyaRNNHALplFLVKLYS------- 176

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1371546634 360 lYNSLNLLMRLHNAGLTHLDLSPDNMLISPKNYEMRLCDLSQS 402
Cdd:PTZ00036  177 -YQLCRALAYIHSKFICHRDLKPQNLLIDPNTHTLKLCDFGSA 218

Catalytic domain of the Serine/Threonine kinase, Mitogen-activated protein kinase signal-integrating kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MAPK signal-integrating kinases (Mnks) are MAPK-activated protein kinases and is comprised by a group of four proteins, produced by alternative splicing from two genes (Mnk1 and Mnk2). The isoforms of Mnk1 (1a/1b) and Mnk2 (2a/2b) differ at their C-termini, with the a-form having a longer C-terminus containing a MAPK-binding region. All Mnks contain a catalytic kinase domain and a polybasic region at the N-terminus which binds importin and the eukaryotic initiation factor eIF4G. The best characterized Mnk substrate is eIF4G, whose phosphorylation may promote the export of certain mRNAs from the nucleus. Mnk also phosphorylate substrates that bind to AU-rich elements that regulate mRNA stability and translation. Mnks have also been implicated in tyrosine kinase receptor signaling, inflammation, and cell prolieration or survival. The Mnk 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 1371546634 320 NGNIVLISEFF--------------GENVFDYIKRKKNtlfvvsdISNEDKKKILYNSLNLLMRLHNAGLTHLDLSPDNM 385
Cdd:cd14174    59 NKNILELIEFFeddtrfylvfeklrGGSILAHIQKRKH-------FNEREASRVVRDIASALDFLHTKGIAHRDLKPENI 131

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1371546634 386 L------ISPknyeMRLCDLSQSTPIytnklrhkeKLNS----IKPFESFEPCiGKIEYIPPECWKIVwkykmnniknpi 455
Cdd:cd14174   132 LcespdkVSP----VKICDFDLGSGV---------KLNSactpITTPELTTPC-GSAEYMAPEVVEVF------------ 185

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1371546634 456 eylknisnqeERKKYYYDVSCaDKYMLGIFFIWM----------------WNNGFIWKCSdpiQDKIFEIFMKSNMDLNK 519
Cdd:cd14174   186 ----------TDEATFYDKRC-DLWSLGVILYIMlsgyppfvghcgtdcgWDRGEVCRVC---QNKLFESIQEGKYEFPD 251

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|
gi 1371546634 520 fimtKSWPH---ELNNLINKLLHMEHRKTVKLSDLSRHPW 556
Cdd:cd14174   252 ----KDWSHissEAKDLISKLLVRDAKERLSAAQVLQHPW 287

Catalytic domain of the Serine/Threonine kinase, Mitogen-activated protein kinase signal-integrating kinase 2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MAPK signal-integrating kinases (Mnks) are MAPK-activated protein kinases and is comprised by a group of four proteins, produced by alternative splicing from two genes (Mnk1 and Mnk2). The isoforms of Mnk1 (1a/1b) and Mnk2 (2a/2b) differ at their C-termini, with the a-form having a longer C-terminus containing a MAPK-binding region. All Mnks contain a catalytic kinase domain and a polybasic region at the N-terminus which binds importin and the eukaryotic initiation factor eIF4G. The best characterized Mnk substrate is eIF4G, whose phosphorylation may promote the export of certain mRNAs from the nucleus. Mnk also phosphorylate substrates that bind to AU-rich elements that regulate mRNA stability and translation. Mnks have also been implicated in tyrosine kinase receptor signaling, inflammation, and cell prolieration or survival. The Mnk 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 1371546634 322 NIVLISEFF--------------GENVFDYIKRKKN-----TLFVVSDISNedkkkilynSLNLLmrlHNAGLTHLDLSP 382
Cdd:cd14173    61 NVLELIEFFeeedkfylvfekmrGGSILSHIHRRRHfneleASVVVQDIAS---------ALDFL---HNKGIAHRDLKP 128

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1371546634 383 DNML------ISPknyeMRLCDLSQSTPIytnklrhkeKLNS----IKPFESFEPCiGKIEYIPPEcwkIVWKYkmnnik 452
Cdd:cd14173   129 ENILcehpnqVSP----VKICDFDLGSGI---------KLNSdcspISTPELLTPC-GSAEYMAPE---VVEAF------ 185

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1371546634 453 npieylknisNQEERkkyYYDVSCaDKYMLGIFFIWMWNN--GFIWKC-SD----------PIQDKIFEIFMKSNMDLNK 519
Cdd:cd14173   186 ----------NEEAS---IYDKRC-DLWSLGVILYIMLSGypPFVGRCgSDcgwdrgeacpACQNMLFESIQEGKYEFPE 251

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|
gi 1371546634 520 fimtKSWPH---ELNNLINKLLHMEHRKTVKLSDLSRHPW 556
Cdd:cd14173   252 ----KDWAHiscAAKDLISKLLVRDAKQRLSAAQVLQHPW 287

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 1371546634 320 NGNIVLISEFF-GENVFDYIKRKKNTLfvvsdiSNEDKKKILYNSLNLLMRLHNAGLTHLDLSPDNMLISpKNYEMRLCD 398
Cdd:cd00180    63 ENFLYLVMEYCeGGSLKDLLKENKGPL------SEEEALSILRQLLSALEYLHSNGIIHRDLKPENILLD-SDGTVKLAD 135

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1371546634 399 LSQSTPIYTNKLRHKEKLNSIKPFESFEPCIGKIEY 434
Cdd:cd00180   136 FGLAKDLDSDDSLLKTTGGTTPPYYAPPELLGGRYY 171

Catalytic kinase domain of Myosin Light Chain Kinase-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This family is composed of MLCKs and related MLCK-like kinase domains from giant STKs such as titin, obscurin, SPEG, Unc-89, Trio, kalirin, and Twitchin. Also included in this family are Death-Associated Protein Kinases (DAPKs) and Death-associated protein kinase-Related Apoptosis-inducing protein Kinase (DRAKs). MLCK phosphorylates myosin regulatory light chain and controls the contraction of all muscle types. Titin, obscurin, Twitchin, and SPEG are muscle proteins involved in the contractile apparatus. The giant STKs are multidomain proteins containing immunoglobulin (Ig), fibronectin type III (FN3), SH3, RhoGEF, PH and kinase domains. Titin, obscurin, Twitchin, and SPEG contain many Ig domain repeats at the N-terminus, while Trio and Kalirin contain spectrin-like repeats. The MLCK-like 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 1371546634 323 IVLISEFF-GENVFDYIKRKkntlFVVSDisnEDKKKILYNSLNLLMRLHNAGLTHLDLSPDNMLISPKNY-EMRLCDLS 400
Cdd:cd14006    64 LVLILELCsGGELLDRLAER----GSLSE---EEVRTYMRQLLEGLQYLHNHHILHLDLKPENILLADRPSpQIKIIDFG 136

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1371546634 401 QSTpiytnKLRHKEKLNSIKpfesfepciGKIEYIPPE 438
Cdd:cd14006   137 LAR-----KLNPGEELKEIF---------GTPEFVAPE 160

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 1371546634 320 NGNIVLISEFF-GENVFDYIKRKKNtlfvvsdISNEDKKKILYNSLNLLMRLHNAGLTHLDLSPDNMLISPKNyEMRLCD 398
Cdd:cd14014    72 DGRPYIVMEYVeGGSLADLLRERGP-------LPPREALRILAQIADALAAAHRAGIVHRDIKPANILLTEDG-RVKLTD 143

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1371546634 399 LSQSTPIYTNKLRHKEKLnsikpfesfepcIGKIEYIPPE 438
Cdd:cd14014   144 FGIARALGDSGLTQTGSV------------LGTPAYMAPE 171

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1371546634 321 GNIVLISEFFGENVFDYIKRKKNTLfvvsdiSNEDKKKILYNSLNLLMRLHNAGLTHLDLSPDNMLISPKNyEMRLCD 398
Cdd:cd07833    73 GRLYLVFEYVERTLLELLEASPGGL------PPDAVRSYIWQLLQAIAYCHSHNIIHRDIKPENILVSESG-VLKLCD 143

Catalytic domain of Dual-specificity tYrosine-phosphorylated and -Regulated Kinase-like protein kinases; Dual-specificity PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine (S/T) as well as tyrosine residues on protein substrates. This subfamily is composed of the dual-specificity DYRKs and YAK1, as well as the S/T kinases (STKs), HIPKs. DYRKs and YAK1 autophosphorylate themselves on tyrosine residues and phosphorylate their substrates exclusively on S/T residues. Proteins in this subfamily play important roles in cell proliferation, differentiation, survival, growth, and development. The DYRK-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 1371546634 294 KNCKKYKFQDLNELN--DILTKKLENNING------------NIVLISEFFGENVFDYIKRKKNTLFVVSDIsnedkKKI 359
Cdd:cd14133    33 KNNKDYLDQSLDEIRllELLNKKDKADKYHivrlkdvfyfknHLCIVFELLSQNLYEFLKQNKFQYLSLPRI-----RKI 107

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1371546634 360 LYNSLNLLMRLHNAGLTHLDLSPDNMLI-SPKNYEMRLCDLSQS 402
Cdd:cd14133   108 AQQILEALVFLHSLGLIHCDLKPENILLaSYSRCQIKIIDFGSS 151

Catalytic domain of the Dual-specificity protein kinases, CDC-like kinases; Dual-specificity PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine (S/T) as well as tyrosine residues on protein substrates. CLKs are involved in the phosphorylation and regulation of serine/arginine-rich (SR) proteins, which play a crucial role in pre-mRNA splicing by directing splice site selection. SR proteins are phosphorylated first by SR protein kinases (SRPKs) at the N-terminus, which leads to its assembly into nuclear speckles where splicing factors are stored. CLKs phosphorylate the C-terminal part of SR proteins, causing the nuclear speckles to dissolve and splicing factors to be recruited at sites of active transcription. Based on a conserved "EHLAMMERILG" signature motif which may be crucial for substrate specificity, CLKs are also referred to as LAMMER kinases. CLKs autophosphorylate at tyrosine residues and phosphorylate their substrates exclusively on S/T residues. In Drosophila, the CLK homolog DOA (Darkener of apricot) is essential for embryogenesis and its mutation leads to defects in sexual differentiation, eye formation, and neuronal development. In fission yeast, the CLK homolog Lkh1 is a negative regulator of filamentous growth and asexual flocculation, and is also involved in oxidative stress response. Vertebrates contain mutliple CLK proteins and mammals have four (CLK1-4). The CLK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1371546634 320 NGNIVLISEFFGENVFDYIKRKKNTLFVVSDIsnedkKKILYNSLNLLMRLHNAGLTHLDLSPDNMLI------------ 387
Cdd:cd14134    86 RGHMCIVFELLGPSLYDFLKKNNYGPFPLEHV-----QHIAKQLLEAVAFLHDLKLTHTDLKPENILLvdsdyvkvynpk 160

                          90
                  ....*....|....*..
gi 1371546634 388 ------SPKNYEMRLCD 398
Cdd:cd14134   161 kkrqirVPKSTDIKLID 177

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1371546634 322 NIVLisEFFGENVFDYIKRKKNTLFVVSDIsneDKKKILYNSLNLLMRLHNAGLTHLDLSPDNMLISPKNYEMRLCD 398
Cdd:cd14137    79 NLVM--EYMPETLYRVIRHYSKNKQTIPII---YVKLYSYQLFRGLAYLHSLGICHRDIKPQNLLVDPETGVLKLCD 150

Catalytic domain of the Serine/Threonine Kinase, Homeodomain-Interacting Protein Kinase 2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. HIPK2, the most studied HIPK, is a coregulator of many transcription factors and cofactors including homeodomain proteins (Nkx and HOX families), Smad1-4, Pax6, c-Myb, AML1, the histone acetyltransferase p300, and the tumor repressor p53, among others. It regulates gene transcription during development and in DNA damage response (DDR), and mediates cell processes such as apoptosis, survival, differentiation, and proliferation. HIPK2 mediates apoptosis by phosphorylating and activating p53 during DDR, resulting in the activation of apoptotic genes. In the absence of p53, HIPK2 targets the anti-apoptotic corepressor C-terminal binding protein (CtBP), leading to CtBP's degradation and the promotion of apoptosis. HIPKs, originally identified by their ability to bind homeobox factors, are nuclear proteins containing catalytic kinase and homeobox-interacting domains as well as a PEST region overlapping with the speckle-retention signal (SRS). The HIPK2 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 1371546634 325 LISEFFGENVFDYIKRKKNTLFVVSDIsnedkKKILYNSLNLLMRLHNAGLTHLDLSPDN-MLISPKN--YEMRLCDLSQ 401
Cdd:cd14227    93 LVFEMLEQNLYDFLKQNKFSPLPLKYI-----RPILQQVATALMKLKSLGLIHADLKPENiMLVDPSRqpYRVKVIDFGS 167

                  ....
gi 1371546634 402 STPI 405
Cdd:cd14227   168 ASHV 171

Catalytic domain of the Dual-specificity protein kinase, CDC-like kinase 2; Dual-specificity PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine as well as tyrosine residues on protein substrates. CLK2 plays a role in hepatic insulin signaling and glucose metabolism. It is induced by the insulin/Akt pathway as part of the hepatic refeeding reponse, and it directly phosphorylates the SR domain of PGC-1alpha, which results in decreased gluconeogenic gene expression and glucose output. CLKs are involved in the phosphorylation and regulation of serine/arginine-rich (SR) proteins, which play a crucial role in pre-mRNA splicing by directing splice site selection. SR proteins are phosphorylated first by SR protein kinases (SRPKs) at the N-terminus, which leads to its assembly into nuclear speckles where splicing factors are stored. CLKs phosphorylate the C-terminal part of SR proteins, causing the nuclear speckles to dissolve and splicing factors to be recruited at sites of active transcription. Based on a conserved "EHLAMMERILG" signature motif which may be crucial for substrate specificity, CLKs are also referred to as LAMMER kinases. CLKs autophosphorylate at tyrosine residues and phosphorylate their substrates exclusively on serine/threonine residues. The CLK2 subfamily is part of a larger superfamily that includes the catalytic domains of other protein serine/threonine PKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1371546634 294 KNCKKYKFQ---DLNELNDILTKKLENN-----------INGNIVLISEFFGENVFDYIKRKKNTLFVVSDIsnedkKKI 359
Cdd:cd14215    47 KNVEKYKEAarlEINVLEKINEKDPENKnlcvqmfdwfdYHGHMCISFELLGLSTFDFLKENNYLPYPIHQV-----RHM 121

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1371546634 360 LYNSLNLLMRLHNAGLTHLDLSPDNMLISPKNYEMR 395
Cdd:cd14215   122 AFQVCQAVKFLHDNKLTHTDLKPENILFVNSDYELT 157