CAMK1 family consists of six family members in human. Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, regulates transcription activators activity, cell cycle, hormone production, cell differentiation, actin filament organization and neurite outgrowth. Family member CAMK1 is a monomeric 42KD enzyme distributed in most mammalian cell types. CAMK1 contains a protein kinase catalytic domain flanked by an ATP bind lobe and protein substrates bind lobe. CAMK1 keeps an inhibited state normally, with the ATP binding lobe interacting with AID domain. Active CAMK1 prefers the substrate containing a basic residue at the P-3 position and a hydrophobic residue at P-5 (1). CAMK1 acts as a key molecule in calcium-triggered CaMKK-CaMK1 signaling cascade and regulates a variety of cellular processes including transcription activators activity, cell cycle, hormone production, cell differentiation, actin filament organization, neurite outgrowth and also involves in regulation of axonal extension and growth cone motility in hippocampal and cerebellar nerve cells (2).

Reference
1. Soderling, T.R. and Stull, J.T. (2001) Structure and regulation of calcium/calmodulin-dependent protein kinases. Chem Rev, 101, 2341-2352. PMID: 11749376
2. Kamata, A., Sakagami, H., Tokumitsu, H., Owada, Y., Fukunaga, K. and Kondo, H. (2007) Spatiotemporal expression of four isoforms of Ca2+/calmodulin-dependent protein kinase I in brain and its possible roles in hippocampal dendritic growth. Neurosci Res, 57, 86-97. PMID: 17056143

    CAMK2 (Calcium/calmodulin-dependent protein kinase type II) belongs to the CAMK group. CAMK2 is a key mediator of Ca2+ signaling. CAMK2 obtains its kinase catalytic activity fowling by binding of Ca2+/Calmodulin on its CAM binding domain. In addition, CAMK2 also undergoes multiple autoregulatory states through phosphorylation of on autoregulatory domain or CAM binding domain. Each phosphorylation state of CAMK2 can regulate related physiological targets (1). Studies show that CAMK2 is involved in sarcoplamic reticulum Ca2+ transport in skeletal muscle and function in dendritic spine and synapse formation and neuronal plasticity (2). CAMK2 also plays an important role in keep de synaptic plasticity which enables LTP and hippocampus-dependent learning (3).

Reference
1. Hudmon, A. and Schulman, H. (2002) Structure-function of the multifunctional Ca2+/calmodulin-dependent protein kinase II. Biochem J, 364, 593-611. PMID: 11931644
2. Rose, A.J., Kiens, B. and Richter, E.A. (2006) Ca2+-calmodulin-dependent protein kinase expression and signalling in skeletal muscle during exercise. J Physiol, 574, 889-903 PMID: 16690701
3. Soderling, T.R. and Stull, J.T. (2001) Structure and regulation of calcium/calmodulin-dependent protein kinases. Chem Rev, 101, 2341-2352. PMID: 11749376

    CAMKL family consists of several subfamily including SNRK, QIK, BRSK, AMPK, MARK, NuaK, NIM1, HUNK, LKB, PASK, MELK and CHK1. They are classified into CAMKL family for the high similarity kinase catalytic domain. AMPK subfamily (AMP-activated protein kinase) consists of three subunits, a catalytic subunit (α) and two regulatory subunits (β and γ). Two catalytic subunits have been identified in mammals. Activation of AMPK is involved in two steps; first, AMP binds to γ-subunit, and second the phosphorylation of threonine 172 by LKB1. Activated AMPK targets a variety of substrates and participates different cellular processes including mTORC1 signaling, phosphorylation of p53 or other tumor suppressors (1). MARK subfamily (microtubule-affinity regulating kinases) consists of four members (MARK1-MARK4) in mammals cells. All isoforms contain a N-terminal header, a catalytic kinase domain, a ubiquitin-associated domain, a spacer domain and a C-terminal KA1 domain. MARKs are discovered for its ability to regulate the stability of microtubules. Studies also show that MARK has some relation with disease, such as Alzheimer's disease (2). Nuak subfamilies are AMPK related kinases. NuaK1 are stress-activated kinase which is involved in tolerance to glucose starvation. NuaK1 can induce cell-cell detachment by increasing F-actin conversion to G-actin. NuaK1 can protect cells from CD95-mediated apoptosis and is required for the increased motility and invasiveness of CD95- activated tumor cells (3).

Reference
1. Luo, Z., Zang, M. and Guo, W. (2010) AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncol, 6, 457-470. PMID: 20222801
2. Matenia, D. and Mandelkow, E.M. (2009) The tau of MARK: a polarized view of the cytoskeleton. Trends Biochem Sci, 34, 332-342. PMID: 19559622
3. Suzuki, A., Kusakai, G., Kishimoto, A., Minegichi, Y., Ogura, T. and Esumi, H. (2003) Induction of cell-cell detachment during glucose starvation through F-actin conversion by SNARK, the fourth member of the AMP-activated protein kinase catalytic subunit family. Biochem Biophys Res Commun, 311, 156-161. PMID: 14575707

    CASK (Calcium/calmodulin-dependent serine protein kinase) belongs to CAMK group. CASK consists of an N-terminal CaM-kinase domain and a C-terminal set of domains including an L27 domain, an SH3 domain and a C-terminal guanylate kinase domain. The PDZ domain binds to neurexins, syndecans, SynCAMs and putative synaptic cell-adhesion molecules. CASK also interacts with protein Ca2+ channels and K2+ channels. In addition, CASK also acts as a nuclear transcription factor. Studies also show that CASK can interact with CAMK2 and regulate its phosphorylation states (1).

Reference
1. Mukherjee, K., Sharma, M., Urlaub, H., Bourenkov, G.P., Jahn, R., Sudhof, T.C. and Wahl, M.C. (2008) CASK Functions as a Mg2+-independent neurexin kinase. Cell, 133, 328-339. PMID: 18423203

    DAPK (Death-associated protein kinase) belongs to the CAMK group. DAPK contains DAPK1, DAPK, Zipper interacting kinase (ZIPK, also named DAPK-3), DAP kinase related apoptosis inducing protein kinase DRAK1 and DRAK2. They share a highly conserved catalytic domain and diverse extracatalytic domains which are associated with different functions. DAPK proteins can activate a variety of downstream cell signaling pathway and then induce cell death via p53 or p53-independent apoptosis or autophagy. In addition, death signal can also stimuli the DAPK cascade signaling pathway and finally induce cell death (1).

Reference
1. Lin, Y., Hupp, T.R. and Stevens, C. (2010) Death-associated protein kinase (DAPK) and signal transduction: additional roles beyond cell death. FEBS J, 277, 48-57. PMID: 19878313

    DCAMKL, Doublecortin-like and CAM kinase-like protein, belong to CAMKL group. Three members have been found in human, DCAMKL1-3. DCAMKL1 may participate in calcium-signaling pathway and control the neuronal migration in the developing brain (1). DCAML2 has little Ca(2+)/CAM affinity compared with other CAMK proteins and may be involved in down regulation of CRE-dependent gene activation via phosphorylating CREB coactivator CRT/TORC2 (2).

Reference
1. Manning, G., Whyte, D.B., Martinez, R., Hunter, T. and Sudarsanam, S. (2002) The protein kinase complement of the human genome. Science, 298, 1912-1934. PMID: 12471243
2. UniProt Annotation: DCLK1_HUMAN
3. UniProt Annotation: DCLK2_HUMAN

    MAPKAPK (MAPK-activated protein kinase) belongs to CAMK group. MAPKAPK is a type of Ser/Thr protein kinases that can be phosphorylated and activated under extracellular stimulation through a MAPK-dependent pathway. Five members have been identified in human genome which are known as the p90 ribosomal S6 kinase(RSK), the mitogen- and stress-activated kinase(MSK), the MAPK-interacting kinase(MNK), the MAPK-activated protein kinase 2/3 (MK2/3) and p32-regulated/activated protein kinase(MK5). Alignment of MAPK-binding sequences forming MAPKAPKs show that regions of C-terminal D domains are present in all MAPKAPKs which is necessary for efficient activation. Activated MAPKAPKs are involved in a variety of cellular processes via phosphorylation of a large rang of substrates such as SRF, Nur77, LKB1, TSC2, DAPK,eIF4G, Spry2, p537 and so on. They play a important role in regulation of gene transcription, cell proliferation, cell growth, cell survival, mRNA translation, cell cycle and tumor suppression (1).

Reference
1. Cargnello, M. and Roux, P.P. (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev, 75, 50-83. PMID: 21372320

    MLCK (myosin light chain kinase) belongs to CAMK group and is Ca2+/calmodulin-dependent serine−threonine protein kinase which can phosphorylate the regulatory light chain of mysosin. Skeletal muscle MLCK contains an N-terminal sequence, a protein kinase catalytic core domain and a regulatory segment which consists of an autoinhibitory sequence and a calmodulin binding sequence. The expression size of MLCK in different animal species is related with diverse N-terminal sequence. The MLCKs are activated via binding with calmodulin which is a highly conserved Ca2+-binding protein (1). NMM (nonmuscle myosin) and SMM (smooth muscle myosin) are known substrates of MLCK in vivo. Phosphorylation of RLC on moysin can activate actin-activated myosin ATPase activity which is essential for muscle contraction. In addition, the phosphorylation functions of MLCKs in tracheal, bronchial and gastrointestinal smooth muscle cannot be replaced by others kinases (2).

Reference
1. Stull, J.T., Kamm, K.E. and Vandenboom, R. (2011) Myosin light chain kinase and the role of myosin light chain phosphorylation in skeletal muscle. Arch Biochem Biophys, 510, 120-128. PMID: 21284933
2. Hong, F., Haldeman, B.D., Jackson, D., Carter, M., Baker, J.E. and Cremo, C.R. (2011) Biochemistry of smooth muscle myosin light chain kinase. Arch Biochem Biophys, 510, 135-146. PMID: 21565153

    PHK refers to the catalytic subunit of the phosphorylase b kinase, which mediates the neural and hormonal regulation of glycogen breakdown (glycogenolysis) by phosphorylating and thereby activating glycogen phosphorylase (PYGB, PYGL or PYGM). PHK may regulate glycogeneolysis in the testis and phosphorylate TNNI3, TNNT2, MAPT/TAU, GAP43 and NRGN/RC3 in vitro (1).

Reference
1. UniProt Annotation:PHKG2_HUMAN

    PIM consists of three members, PIM-1, PIM-2 and PIM-3. Sequence analysis shows that PIM-1 and PIM-2 share a sequence identity of 61%, whereas PIM-1 and PIM-3 are 77%. PIM kinases play an important role in cancer. PIM-1 and PIM-2 transgenic mice overexpression these genes have been observed to develop lymphomas. In addition, PIM-1 is over expressed in c-myc transgene driven prostate tumors in mice. In human, PIM-1 and PIM-2 are involved in prostate cancer development. Studies show that PIM-3 is over expressed in colorectal, pancreatic and hepatocellular carcinoma. The mechanisms that PIMs implicated in cancer have been reported that PIMs act as key regulator in several major proliferative and survival signaling pathways or influence the activity of specific cell cycle molecules and changes in gene expression (1).

Reference
1. Isaac, M., Siu, A. and Jongstra, J. (2011) The oncogenic PIM kinase family regulates drug resistance through multiple mechanisms. Drug Resist Updat, 14, 203-211. PMID: 21601509

    PKD belongs to CAMK group. PKD contains three genes in mammals known as, PKD1, PKD2 and PKD3. Sequence analysis shows that PKDs contain two DAG-type domains (C1 and C2 domain) which are followed by a PH domain and C-terminal protein kinase catalytic domain. Activated PKC recruits PKD through C1 domain and causes the PKD activation loop phosphorylation which induces a conformational change. PKDs act as key regulator which are involved in a variety of cell physiology including cell survival after oxidative stress, inhibition of cell migration, gene transcription and golgi-vesicle fission and transport (1).

Reference
1. Fu, Y. and Rubin, C.S. (2011) Protein kinase D: coupling extracellular stimuli to the regulation of cell physiology. EMBO Rep, 12, 785-796. PMID: 21738220

    PSK belongs to CAMK group and two genes encoding the PSKs have been identified in human genome which are known as PSKH1 and PSKH2. PSKH1 have been shown to target in SFC (splicing factor compartments) through its kinase catalytic domain and C-terminal domains. Migration of PSKH1-FLAG into SFCs is enhanced during co-expression of T7-tagged ASF/SF2 and others members of SR protein family. In addition, overexpression of PSKH1 has been reported to have an important affects on splicing of an E1A minigene (1).

Reference
1. Brede, G., Solheim, J. and Prydz, H. (2002) PSKH1, a novel splice factor compartment-associated serine kinase. Nucleic Acids Res, 30, 5301-5309. PMID: 12466556

    RAD53, also known as Checkpoint kinase 2, is a key kinase which is required in checkpoint-mediated cell cycle related processes. When damage response occurred, Mec1 protein is recruited to bind DNA and triggers the downstream signal cascade. Rad9 is activated via phosphorylation by Mec1 and as a result RAD53 binds to Rad9 with the phospho-binding domain FHA and undergoes autophosphorylation events which are important on activation of Rad53. Activated RAD53 amplifies the original signals and triggers the downstream events of checkpoint activation including cell cycle delay, DNA repair, replication fork stabilization and fork restart processes (1).

Reference
1. Branzei, D. and Foiani, M. (2006) The Rad53 signal transduction pathway: Replication fork stabilization, DNA repair, and adaptation. Exp Cell Res, 312, 2654-2659. PMID: 16859682

    Trbl belongs to CAMK group. Three genes encoding trbl have been identified in mammals, and the related orthologus also been found in vertebrates and invertebrates. The Trbl kinases share a conserved central kinase catalytic domain flanked by not unclosely related N-terminal and C-terminal sequences. However, the kinase domains lack the key active site lysine and might be an inactive kinase. Studies show that Trbl kinases are key molecule function on controlling Mitogen-activated protein kinase cascades. For instance, human trbl-1 overexpression can modulate the activation of Ras/MEK-1/ERK pathway, and some MAPKK interacts with Trbls which results enhance of kinase activation (1).

Reference
1. Kiss-Toth, E., Bagstaff, S.M., Sung, H.Y., Jozsa, V., Dempsey, C., Caunt, J.C., Oxley, K.M., Wyllie, D.H., Polgar, T., Harte, M. et al. (2004) Human tribbles, a protein family controlling mitogen-activated protein kinase cascades. J Biol Chem, 279, 42703-42708. PMID: 15299019

    Trio is present in eumetazoa and the kinase domain does not always exist. Nematode copies lack the C-terminal kinase domain meanwhile a subset of insects including Drosophilids and mosquitoes, lost the kinase domain and the adjacent lg and FN3 domains. Two human related Trio genes, Trio and Trad, encode long proteins both of which contain Sec 14, Spectrin RhoGEF, SH3, PH, Ig, FN3 and Kinase domains (1). The function of Trio is very important for development; it can mediate the fine-scale mapping of neuronal cell positions once the global arrangement of the brain has been established. Moreover, Trio is also able to interact with distinct signal partners. In Drosophila, the Rac-specific GEF1 of Trio appears to be the major signaling domain for retinal developmental processes, and Trio/Rac pathway is critical for RPTP signaling. In addition, Trio could interact with pak and they can operate in a common pathway to regulate retinal axon guidance (2) .

Reference
1. Wikinome Annotation:   Kinase Family Trio
2. Bateman, J. and Van Vactor, D. (2001) The Trio family of guanine-nucleotide-exchange factors: regulators of axon guidance. JJ Cell Sci, 114, 1973-1980. PMID: 15299019

    TSSK (testis-specific serine kinase) belongs to CAMK group. Six members have been identified in this family in human genome.However, only five possess kinase catalytic domain including TSSK1, TSSK2, TSSK3, TSSK4 and TSSK6. TSSKs contain a kinase domain and a variable short C-terminal extension. All members contain a conserved activation loop threonine phosphorylation site. Two members TSSK2 and TSSK3 can undergo autophosphorylation. TSSK1 and TSSK2 are formed by tandem duplication and a dual knockout is infertile as a heterozygote. TSSK3 is expressed only in interstitial Leydig cells, which contrasts with the expression of TSSK1 and TSSK2 in late spermatids and sperm. TSSK4 can bind to CREB by Y2H and can phosphorylate and activate CREB in human and mouse cells (1).

Reference
1. Wikinome Annotation:    Kinase Family TSSK