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 405133345  51 DWEQLCLLQPLGSGGFGSVYKATYHGATVAVKQVKKSSKNRlASRQSFWAELNVARLQHANVVRVVAASTCapASQNSLG 130
Cdd:cd13979    1 DWEPLRLQEPLGSGGFGSVYKATYKGETVAVKIVRRRRKNR-ASRQSFWAELNAARLRHENIVRVLAAETG--TDFASLG 77

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 405133345 131 TIIMEYVGNITLHHVIYGTSDtwrqgeedeggcgkkALSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd13979   78 LIIMEYCGNGTLQQLIYEGSE---------------PLPLAHRILISLDIARALRFCHSHGIV 125

Catalytic domain of the Serine/Threonine kinase, Oocyte maturation factor Mos; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Mos (or c-Mos) is a germ-cell specific kinase that plays roles in both the release of primary arrest and the induction of secondary arrest in oocytes. It is expressed towards the end of meiosis I and is quickly degraded upon fertilization. It is a component of the cytostatic factor (CSF), which is responsible for metaphase II arrest. In addition, Mos activates a phoshorylation cascade that leads to the activation of the p34 subunit of MPF (mitosis-promoting factor or maturation promoting factor), a cyclin-dependent kinase that is responsible for the release of primary arrest in meiosis I. The Mos subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345  51 DWEQLCLLQPLGSGGFGSVYKATYHGATVAVKQVKKSSKNRlASRQSFWAELNVARLQHANVVRVVAASTCapASQNSLG 130
Cdd:cd13979    1 DWEPLRLQEPLGSGGFGSVYKATYKGETVAVKIVRRRRKNR-ASRQSFWAELNAARLRHENIVRVLAAETG--TDFASLG 77

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 405133345 131 TIIMEYVGNITLHHVIYGTSDtwrqgeedeggcgkkALSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd13979   78 LIIMEYCGNGTLQQLIYEGSE---------------PLPLAHRILISLDIARALRFCHSHGIV 125

Serine/threonine protein kinase [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345  57 LLQPLGSGGFGSVYKATYH--GATVAVKQVKKSSKNRLASRQSFWAELNV-ARLQHANVVRVVAASTcapasQNSLGTII 133
Cdd:COG0515   11 ILRLLGRGGMGVVYLARDLrlGRPVALKVLRPELAADPEARERFRREARAlARLNHPNIVRVYDVGE-----EDGRPYLV 85

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345 134 MEYVGNITLHHVIygtsdtwrqgeeDEGGcgkkALSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:COG0515   86 MEYVEGESLADLL------------RRRG----PLPPAEALRILAQLAEALAAAHAAGIV 129

Stk1 family PASTA domain-containing Ser/Thr kinase;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345  57 LLQPLGSGGFGSVYKA--TYHGATVAVKqVKKSSknrLASRQSFWA----E-LNVARLQHANVVRV--VAastcapaSQN 127
Cdd:NF033483  11 IGERIGRGGMAEVYLAkdTRLDRDVAVK-VLRPD---LARDPEFVArfrrEaQSAASLSHPNIVSVydVG-------EDG 79

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 405133345 128 SLGTIIMEYVGNITLHHVIygtsdtwrqgeeDEGGcgkkALSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:NF033483  80 GIPYIVMEYVDGRTLKDYI------------REHG----PLSPEEAVEIMIQILSALEHAHRNGIV 129

Catalytic domain of the Serine/Threonine kinase, Oocyte maturation factor Mos; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Mos (or c-Mos) is a germ-cell specific kinase that plays roles in both the release of primary arrest and the induction of secondary arrest in oocytes. It is expressed towards the end of meiosis I and is quickly degraded upon fertilization. It is a component of the cytostatic factor (CSF), which is responsible for metaphase II arrest. In addition, Mos activates a phoshorylation cascade that leads to the activation of the p34 subunit of MPF (mitosis-promoting factor or maturation promoting factor), a cyclin-dependent kinase that is responsible for the release of primary arrest in meiosis I. The Mos subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345  51 DWEQLCLLQPLGSGGFGSVYKATYHGATVAVKQVKKSSKNRlASRQSFWAELNVARLQHANVVRVVAASTCapASQNSLG 130
Cdd:cd13979    1 DWEPLRLQEPLGSGGFGSVYKATYKGETVAVKIVRRRRKNR-ASRQSFWAELNAARLRHENIVRVLAAETG--TDFASLG 77

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 405133345 131 TIIMEYVGNITLHHVIYGTSDtwrqgeedeggcgkkALSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd13979   78 LIIMEYCGNGTLQQLIYEGSE---------------PLPLAHRILISLDIARALRFCHSHGIV 125

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 405133345  61 LGSGGFGSVYKATY--HGATVAVKQVKKSSKNRLasRQSFWAELNV-ARLQHANVVRVVAASTcapaSQNSLGtIIMEYV 137
Cdd:cd00180    1 LGKGSFGKVYKARDkeTGKKVAVKVIPKEKLKKL--LEELLREIEIlKKLNHPNIVKLYDVFE----TENFLY-LVMEYC 73

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 405133345 138 GNITLHHVIygtsdtwrqgEEDEGGcgkkaLSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd00180   74 EGGSLKDLL----------KENKGP-----LSEEEALSILRQLLSALEYLHSNGII 114

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 405133345  61 LGSGGFGSVYKATYHGATVAVKQVKKSSKNRLASRQsFWAELNV-ARLQHANVVRVVAASTcapaSQNSLgTIIMEYVGN 139
Cdd:cd13999    1 IGSGSFGEVYKGKWRGTDVAIKKLKVEDDNDELLKE-FRREVSIlSKLRHPNIVQFIGACL----SPPPL-CIVTEYMPG 74

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 405133345 140 ITLHHVIYGTsdtwrqgeedeggcgKKALSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd13999   75 GSLYDLLHKK---------------KIPLSWSLRLKIALDIARGMNYLHSPPII 113

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345  60 PLGSGGFGSVYKATYHG-----ATVAVKQVKKSSKNrlASRQSFWAELNV-ARLQHANVVRVVAASTcapaSQNSLgTII 133
Cdd:cd00192    2 KLGEGAFGEVYKGKLKGgdgktVDVAVKTLKEDASE--SERKDFLKEARVmKKLGHPNVVRLLGVCT----EEEPL-YLV 74

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345 134 MEYVGNITLHHVIygtsdtwRQGEEDEGGCGKKALSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd00192   75 MEYMEGGDLLDFL-------RKSRPVFPSPEPSTLSLKDLLSFAIQIAKGMEYLASKKFV 127

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345    55 LCLLQPLGSGGFGSVYKATY------HGATVAVKQVKKSSKNrlASRQSFWAELNV-ARLQHANVVRVVAASTcapasQN 127
Cdd:smart00221   1 LTLGKKLGEGAFGEVYKGTLkgkgdgKEVEVAVKTLKEDASE--QQIEEFLREARImRKLDHPNIVKLLGVCT-----EE 73

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 405133345   128 SLGTIIMEYVGNITLHHVIygtsdtwRQgeedeggCGKKALSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:smart00221  74 EPLMIVMEYMPGGDLLDYL-------RK-------NRPKELSLSDLLSFALQIARGMEYLESKNFI 125

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345    55 LCLLQPLGSGGFGSVYKATY------HGATVAVKQVKKSSKNrlASRQSFWAELNV-ARLQHANVVRVVAASTcapaSQN 127
Cdd:smart00219   1 LTLGKKLGEGAFGEVYKGKLkgkggkKKVEVAVKTLKEDASE--QQIEEFLREARImRKLDHPNVVKLLGVCT----EEE 74

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 405133345   128 SLgTIIMEYVGNITLHHVIYGTsdtwrqgeedeggcgKKALSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:smart00219  75 PL-YIVMEYMEGGDLLSYLRKN---------------RPKLSLSDLLSFALQIARGMEYLESKNFI 124

Catalytic domain of C-terminal Src kinase-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. This subfamily is composed of Csk, Chk, and similar proteins. They are cytoplasmic (or nonreceptor) PTKs containing the Src homology domains, SH3 and SH2, N-terminal to the catalytic tyr kinase domain. They negatively regulate the activity of Src kinases that are anchored to the plasma membrane. To inhibit Src kinases, Csk and Chk are translocated to the membrane via binding to specific transmembrane proteins, G-proteins, or adaptor proteins near the membrane. Csk catalyzes the tyr phosphorylation of the regulatory C-terminal tail of Src kinases, resulting in their inactivation. Chk inhibit Src kinases using a noncatalytic mechanism by simply binding to them. As negative regulators of Src kinases, Csk and Chk play important roles in cell proliferation, survival, and differentiation, and consequently, in cancer development and progression. The Csk-like subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345  50 IDWEQLCLLQPLGSGGFGSVYKATYHGATVAVKQVKKSSKnrlaSRQSFWAELNV-ARLQHANVVRVVAASTcapaSQNS 128
Cdd:cd05039    3 INKKDLKLGELIGKGEFGDVMLGDYRGQKVAVKCLKDDST----AAQAFLAEASVmTTLRHPNLVQLLGVVL----EGNG 74

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 405133345 129 LgTIIMEYVGNITLhhVIYGTSDtwrqgeedeggcGKKALSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd05039   75 L-YIVTEYMAKGSL--VDYLRSR------------GRAVITRKDQLGFALDVCEGMEYLESKKFV 124

Catalytic (repeat 2) domain of the Protein Tyrosine Kinases, Janus kinases; The Jak subfamily is composed of Jak1, Jak2, Jak3, TYK2, and similar proteins. They are PTKs, catalyzing the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Jaks are cytoplasmic (or nonreceptor) PTKs containing an N-terminal FERM domain, followed by a Src homology 2 (SH2) domain, a pseudokinase domain, and a C-terminal tyr kinase catalytic domain. Most Jaks are expressed in a wide variety of tissues, except for Jak3, which is expressed only in hematopoietic cells. Jaks are crucial for cytokine receptor signaling. They are activated by autophosphorylation upon cytokine-induced receptor aggregation, and subsequently trigger downstream signaling events such as the phosphorylation of signal transducers and activators of transcription (STATs). Jaks are also involved in regulating the surface expression of some cytokine receptors. The Jak-STAT pathway is involved in many biological processes including hematopoiesis, immunoregulation, host defense, fertility, lactation, growth, and embryogenesis. The Jak subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345  53 EQLCLLQPLGSGGFGSVYKATY------HGATVAVKQVKKSSKNrlASRQSFWAELNVAR-LQHANVVRVVAasTCAPAS 125
Cdd:cd05038    4 RHLKFIKQLGEGHFGSVELCRYdplgdnTGEQVAVKSLQPSGEE--QHMSDFKREIEILRtLDHEYIVKYKG--VCESPG 79

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 405133345 126 QNSLGtIIMEYVGnitlhhviYGTSDTWRQGEEDEggcgkkaLSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd05038   80 RRSLR-LIMEYLP--------SGSLRDYLQRHRDQ-------IDLKRLLLFASQICKGMEYLGSQRYI 131

Catalytic domain of the Serine/Threonine kinase, eukaryotic translation Initiation Factor 2-Alpha Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. EIF2AKs phosphorylate the alpha subunit of eIF-2, resulting in the downregulation of protein synthesis. eIF-2 phosphorylation is induced in response to cellular stresses including virus infection, heat shock, nutrient deficiency, and the accummulation of unfolded proteins, among others. There are four distinct kinases that phosphorylate eIF-2 and control protein synthesis under different stress conditions: General Control Non-derepressible-2 (GCN2) which is activated during amino acid or serum starvation; protein kinase regulated by RNA (PKR) which is activated by double stranded RNA; heme-regulated inhibitor kinase (HRI) which is activated under heme-deficient conditions; and PKR-like endoplasmic reticulum kinase (PERK) which is activated when misfolded proteins accumulate in the ER. The EIF2AK subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345  61 LGSGGFGSVYKATYH--GATVAVKQVKKSSKNRLASRQSFWAELNvARLQHANVVRVVAAstcapASQNSLGTIIMEYVG 138
Cdd:cd13996   14 LGSGGFGSVYKVRNKvdGVTYAIKKIRLTEKSSASEKVLREVKAL-AKLNHPNIVRYYTA-----WVEEPPLYIQMELCE 87

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 405133345 139 NITLHHVIygtsdtwrqgeedegGCGKKALSLEETVCYSC--DILTGLAFLHSQGIV 193
Cdd:cd13996   88 GGTLRDWI---------------DRRNSSSKNDRKLALELfkQILKGVSYIHSKGIV 129

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 405133345  56 CLLQPLGSGGFGSVYKATY--HGATVAVKQVKKSSKnrlASRQSFWAELNVAR-LQHANVVRVvaastcapasqnsLGT- 131
Cdd:cd05122    3 EILEKIGKGGFGVVYKARHkkTGQIVAIKKINLESK---EKKESILNEIAILKkCKHPNIVKY-------------YGSy 66

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 405133345 132 -------IIMEYVGNITLHHVIYGTSDTwrqgeedeggcgkkaLSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd05122   67 lkkdelwIVMEFCSGGSLKDLLKNTNKT---------------LTEQQIAYVCKEVLKGLEYLHSHGII 120

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345  61 LGSGGFGSVYKAT--YHGATVAVKQVKKSSKNRLASRQSFWAELNV-ARLQHANVVRVVAastCAPASQNSLgtIIMEYV 137
Cdd:cd14099    9 LGKGGFAKCYEVTdmSTGKVYAGKVVPKSSLTKPKQREKLKSEIKIhRSLKHPNIVKFHD---CFEDEENVY--ILLELC 83

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 405133345 138 GNITLHHVIYgtsdtwRQgeedeggcgkKALSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd14099   84 SNGSLMELLK------RR----------KALTEPEVRYFMRQILSGVKYLHSNRII 123

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 405133345  61 LGSGGFGSVYKA--TYHGATVAVKQVKKSSKNRLASRQSFWAELNVA------------RLQHANVVRVVAAstCAPASQ 126
Cdd:cd14008    1 LGRGSFGKVKLAldTETGQLYAIKIFNKSRLRKRREGKNDRGKIKNAlddvrreiaimkKLDHPNIVRLYEV--IDDPES 78

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 405133345 127 NSLgTIIMEYVGNITLhhviygtsdtwrqgEEDEGGCGKKALSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd14008   79 DKL-YLVLEYCEGGPV--------------MELDSGDRVPPLPEETARKYFRDLVLGLEYLHENGIV 130

Catalytic domain of the Serine/Threonine Kinases, Bone Morphogenetic Protein and Anti-Muellerian Hormone Type II Receptors; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. BMPR2 and AMHR2 belong to a group of receptors for the TGFbeta family of secreted signaling molecules that includes TGFbeta, BMPs, activins, growth and differentiation factors (GDFs), and AMH, among others. These receptors contain an extracellular domain that binds ligands, a single transmembrane region, and a cytoplasmic catalytic kinase domain. Type II receptors are high-affinity receptors which bind ligands, autophosphorylate, as well as trans-phosphorylate and activate low-affinity type I receptors. BMPR2 and AMHR2 act primarily as a receptor for BMPs and AMH, respectively. BMPs induce bone and cartilage formation, as well as regulate tooth, kidney, skin, hair, haematopoietic, and neuronal development. Mutations in BMPR2A is associated with familial pulmonary arterial hypertension. AMH is mainly responsible for the regression of Mullerian ducts during male sex differentiation. It is expressed exclusively by somatic cells of the gonads. Mutations in either AMH or AMHR2 cause persistent Mullerian duct syndrome (PMDS), a rare form of male pseudohermaphroditism characterized by the presence of Mullerian derivatives (ovary and tubes) in otherwise normally masculine males. The BMPR2/AMHR2 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 405133345  59 QPLGSGGFGSVYKATYHGATVAVKQVKKSsknrlaSRQSFWAELNVARL---QHANVVRVVAASTCAPASQNSLGTIIME 135
Cdd:cd14054    1 QLIGQGRYGTVWKGSLDERPVAVKVFPAR------HRQNFQNEKDIYELplmEHSNILRFIGADERPTADGRMEYLLVLE 74

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 405133345 136 YVGNITLHHVIYGTSDTWRQgeedeggCGKKALSLEEtvcyscdiltGLAFLHS 189
Cdd:cd14054   75 YAPKGSLCSYLRENTLDWMS-------SCRMALSLTR----------GLAYLHT 111

Catalytic domain of Fungal Halotolerance protein 4-like Serine/Threonine kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of HAL4, Saccharomyces cerevisiae Ptk2/Stk2, and similar fungal proteins. Proteins in this subfamily are involved in regulating ion transporters. In budding and fission yeast, HAL4 promotes potassium ion uptake, which increases cellular resistance to other cations such as sodium, lithium, and calcium ions. HAL4 stabilizes the major high-affinity K+ transporter Trk1 at the plasma membrane under low K+ conditions, which prevents endocytosis and vacuolar degradation. Budding yeast Ptk2 phosphorylates and regulates the plasma membrane H+ ATPase, Pma1. The HAL4-like subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345  61 LGSGGFGSV----YKATYHGATVAVKQVKKSSKNRLAS--RQSFWAELNVAR-LQHANVVRVVaastCAPASQNSLGTII 133
Cdd:cd13994    1 IGKGATSVVrivtKKNPRSGVLYAVKEYRRRDDESKRKdyVKRLTSEYIISSkLHHPNIVKVL----DLCQDLHGKWCLV 76

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345 134 MEYVGNITLHHVIygtsdtwrqgEEDeggcgkKALSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd13994   77 MEYCPGGDLFTLI----------EKA------DSLSLEEKDCFFKQILRGVAYLHSHGIA 120

Catalytic domain of the Protein Tyrosine Kinase, Lyn; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Lyn is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lyn is expressed in B lymphocytes and myeloid cells. It exhibits both positive and negative regulatory roles in B cell receptor (BCR) signaling. Lyn, as well as Fyn and Blk, promotes B cell activation by phosphorylating ITAMs (immunoreceptor tyr activation motifs) in CD19 and in Ig components of BCR. It negatively regulates signaling by its unique ability to phosphorylate ITIMs (immunoreceptor tyr inhibition motifs) in cell surface receptors like CD22 and CD5. Lyn also plays an important role in G-CSF receptor signaling by phosphorylating a variety of adaptor molecules. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The Lyn subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345  46 AWcSIDWEQLCLLQPLGSGGFGSVYKATYHGAT-VAVKQVKKSSknrlASRQSFWAELNVAR-LQHANVVRVVAASTcap 123
Cdd:cd05072    1 AW-EIPRESIKLVKKLGAGQFGEVWMGYYNNSTkVAVKTLKPGT----MSVQAFLEEANLMKtLQHDKLVRLYAVVT--- 72

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345 124 asQNSLGTIIMEYVGNITLHHVIygtsdtwrqgEEDEGGcgkkALSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd05072   73 --KEEPIYIITEYMAKGSLLDFL----------KSDEGG----KVLLPKLIDFSAQIAEGMAYIERKNYI 126

Catalytic domain of the Dual-specificity protein kinase, TNNI3-interacting kinase; Dual-specificity PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine as well as tyrosine residues on protein substrates. TNNI3K, also called cardiac ankyrin repeat kinase (CARK), is a cardiac-specific troponin I-interacting kinase that promotes cardiac myogenesis, improves cardiac performance, and protects the myocardium from ischemic injury. It contains N-terminal ankyrin repeats, a catalytic kinase domain, and a C-terminal serine-rich domain. TNNI3K exerts a disease-accelerating effect on cardiac dysfunction and reduced survival in mouse models of cardiomyopathy. The TNNI3K 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 405133345  61 LGSGGFGSVYKATYHGATVAVKQVKKSSKNRLASRQSFWAELNV-ARLQHANVVRVVAASTCAPasqnSLGTIIMEYVGN 139
Cdd:cd14064    1 IGSGSFGKVYKGRCRNKIVAIKRYRANTYCSKSDVDMFCREVSIlCRLNHPCVIQFVGACLDDP----SQFAIVTQYVSG 76

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 405133345 140 ITLHHVIYGTsdtwrqgeedeggcgKKALSLEETVCYSCDILTGLAFLH 188
Cdd:cd14064   77 GSLFSLLHEQ---------------KRVIDLQSKLIIAVDVAKGMEYLH 110

Catalytic domain of the Serine/Threonine Kinases, Mitogen-Activated Protein Kinase Kinase Kinases 12 and 13; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MAP3K12 is also called MAPK upstream kinase (MUK), dual leucine zipper-bearing kinase (DLK) or leucine-zipper protein kinase (ZPK). It is involved in the c-Jun N-terminal kinase (JNK) pathway that directly regulates axonal regulation through the phosphorylation of microtubule-associated protein 1B (MAP1B). It also regulates the differentiation of many cell types including adipocytes and may play a role in adipogenesis. MAP3K13, also called leucine zipper-bearing kinase (LZK), directly phosphorylates and activates MKK7, which in turn activates the JNK pathway. It also activates NF-kB through IKK activation and this activity is enhanced by antioxidant protein-1 (AOP-1). MAP3Ks (MKKKs or MAPKKKs) phosphorylate and activate MAP2Ks (MAPKKs or MKKs), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. The MAP3K12/13 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345  61 LGSGGFGSVYKATYHGATVAVKQVKKSSKNRLAsrqsfwaelNVARLQHANVVRVVAASTCAPASqnslgTIIMEYVGNI 140
Cdd:cd14059    1 LGSGAQGAVFLGKFRGEEVAVKKVRDEKETDIK---------HLRKLNHPNIIKFKGVCTQAPCY-----CILMEYCPYG 66

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 405133345 141 TLHHVIygtsdtwRQGEEdeggcgkkaLSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd14059   67 QLYEVL-------RAGRE---------ITPSLLVDWSKQIASGMNYLHLHKII 103

Catalytic domain of the Protein Tyrosine Kinases, Vascular Endothelial Growth Factor Receptors; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The VEGFR subfamily consists of VEGFR1 (Flt1), VEGFR2 (Flk1), VEGFR3 (Flt4), and similar proteins. VEGFR subfamily members are receptor PTKss (RTKs) containing an extracellular ligand-binding region with seven immunoglobulin (Ig)-like domains, a transmembrane segment, and an intracellular catalytic domain. In VEGFR3, the fifth Ig-like domain is replaced by a disulfide bridge. The binding of VEGFRs to their ligands, the VEGFs, leads to receptor dimerization, activation, and intracellular signaling. There are five VEGF ligands in mammals, which bind, in an overlapping pattern to the three VEGFRs, which can form homo or heterodimers. VEGFRs regulate the cardiovascular system. They are critical for vascular development during embryogenesis and blood vessel formation in adults. They induce cellular functions common to other growth factor receptors such as cell migration, survival, and proliferation. The VEGFR subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345  53 EQLCLLQPLGSGGFGSVYKATYHG-------ATVAVKQVKKSSknRLASRQSFWAELNVARL--QHANVVRVVAASTcap 123
Cdd:cd05054    7 DRLKLGKPLGRGAFGKVIQASAFGidksatcRTVAVKMLKEGA--TASEHKALMTELKILIHigHHLNVVNLLGACT--- 81

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 405133345 124 aSQNSLGTIIMEYV--GNI-----TLHHVIYGTSDTWR---QGEEDEGGCGKKALSLEETVCYSCDILTGLAFLHSQ 190
Cdd:cd05054   82 -KPGGPLMVIVEFCkfGNLsnylrSKREEFVPYRDKGArdvEEEEDDDELYKEPLTLEDLICYSFQVARGMEFLASR 157

Catalytic domain of the LIM domain kinase-like protein kinases; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine or tyrosine residues on protein substrates. Members of this subfamily include LIMK, Testicular or testis-specific protein kinase (TESK), and similar proteins. LIMKs are characterized as serine/threonine kinases (STKs) while TESKs are dual-specificity protein kinases. Both LIMK and TESK phosphorylate and inactivate cofilin, an actin depolymerizing factor, to induce the reorganization of the actin cytoskeleton. They are implicated in many cellular functions including cell spreading, motility, morphogenesis, meiosis, mitosis, and spermatogenesis. The LIMK-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 405133345  61 LGSGGFGSVYKATyHGATVAVKQVKKSSknRLASRQSFWAELNVAR-LQHANVVRVVAasTCAPASQNSLgtiIMEYVGN 139
Cdd:cd14065    1 LGKGFFGEVYKVT-HRETGKVMVMKELK--RFDEQRSFLKEVKLMRrLSHPNILRFIG--VCVKDNKLNF---ITEYVNG 72

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 405133345 140 ITLHHVIYGTSDTwrqgeedeggcgkkaLSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd14065   73 GTLEELLKSMDEQ---------------LPWSQRVSLAKDIASGMAYLHSKNII 111

Catalytic domain of the Serine/Threonine Kinases, fungal Byr2-like Mitogen-Activated Protein Kinase Kinase Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Members of this group include the MAPKKKs Schizosaccharomyces pombe Byr2, Saccharomyces cerevisiae and Cryptococcus neoformans Ste11, and related proteins. They contain an N-terminal SAM (sterile alpha-motif) domain, which mediates protein-protein interaction, and a C-terminal catalytic domain. MAPKKKs phosphorylate and activate MAPK kinases, which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. Fission yeast Byr2 is regulated by Ras1. It responds to pheromone signaling and controls mating through the MAPK pathway. Budding yeast Ste11 functions in MAPK cascades that regulate mating, high osmolarity glycerol, and filamentous growth responses. The Byr2 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 405133345  61 LGSGGFGSVYKA--TYHGATVAVKQVK------KSSKNRLASRQSFWAELNVAR-LQHANVVRVVAASTcapaSQNSLgT 131
Cdd:cd06628    8 IGSGSFGSVYLGmnASSGELMAVKQVElpsvsaENKDRKKSMLDALQREIALLReLQHENIVQYLGSSS----DANHL-N 82

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 405133345 132 IIMEYV--GNITLHHVIYGtsdtwrqgeedeggcgkkalSLEETVCYSC--DILTGLAFLHSQGIV 193
Cdd:cd06628   83 IFLEYVpgGSVATLLNNYG--------------------AFEESLVRNFvrQILKGLNYLHNRGII 128

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 405133345  57 LLQPLGSGGFGSVYKAtYH---GATVAVKQVKKSSKNRLASRQsFWAELNVAR-LQHANVVR---VVAastcapaSQNSL 129
Cdd:cd14003    4 LGKTLGEGSFGKVKLA-RHkltGEKVAIKIIDKSKLKEEIEEK-IKREIEIMKlLNHPNIIKlyeVIE-------TENKI 74

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 405133345 130 GtIIMEYVGNITLHHVIygtsdtwrqgeedeggCGKKALSLEETVCYSCDILTGLAFLHSQGIV 193
Cdd:cd14003   75 Y-LVMEYASGGELFDYI----------------VNNGRLSEDEARRFFQQLISAVDYCHSNGIV 121