Akt, also known as protein kinase B or PKB, is a Serine/Threonine protein kinase family. Akt is composed of three isoforms Akt1, Akt2 and Akt3. Akt is recruited to membrane and activated by PDK1 at the downstream of PI3K pathway. Activated Akt phosphorylates a range of downstream substrates such as IRS1, GSK3, mTOR, p21CIP1, p27KIP1, BAD, ASK1, eNOS and so on. Regulation of these substrates by Akt contributes to varieties of cellular processes, including metabolism, translation, proliferation, survival and angiogene. Akt plays a critial role in regulation of important cellular processes, so dysregulated Akt or abnormal expression of Akt gene will contribute a lot of diseases, including cancer, diabetes, cardiovascular and neurological diseases. As central role in cell signaling and disease, the efforts to identify cell permeant Akt inhibitors have been paid all the time. Several regions on Akt proteins are regarded as drug target site and many inhibitors can successfully target in Akt kinase, including ATP-competitive protein kinase inhibitors and Allosteric inhibitors. The research on Akt will give a new sight into disease and the way to cure them (1).

Reference
1. Hers, I., Vincent, E.E. and Tavare, J.M. (2011) Akt signalling in health and disease. Cell Signal, 23, 1515-1527. PMID: 21620960

    DMPK (myotonic dystrophy protein kinase) belongs to AGC group, which was first described in 1909 and has relation with myotonic dystrophy. The phylogenetic tree of DMPK family shows this family also includes ROCKs (Rho kinases), MRCK (cell division control protein 42 (Cdc42)-binding kinases) and citron kinase. Sequence analysis shows that these kinases contain an amino-terminal kinase catalytic domain followed by a coiled-coil-forming region and other functional motifs at the C-terminus. DMPK has been probed by synthetic peptides or putative physiological substrates to possess Serine/Threonine kinase activity. Many proteins targeted by DMPK show a consensus motif R x x S/T L/V R, which is similar to PKC. DMPK has been shown to act as a key molecule in regulation these in varieties of cellular processes, including regulation of skeletal muscle proper structure and function, ion-channel gating control and cell metabolism. In addition, abnormal expression or genetic defect of DMPK is associated with myotonic dystrophy (1).

Reference
1. Kaliman, P. and Llagostera, E. (2008) Myotonic dystrophy protein kinase (DMPK) and its role in the pathogenesis of myotonic dystrophy 1. Cell Signal, 20, 1935-1941. PMID: 18583094

    GRK (G protein-coupled receptor (GPCR) kinase), belongs to the AGC group and is characterized by its role in relation with GPCR. GPCRs are multi-domain proteins, including an N-termainal unique region, a regulator of G protein signaling (RGS) homology domain (RH) and a kinase catalytic domain. The C-terminal domain is involved in their membrane targeting. GRK isoforms have been shown to target to specialized membrane compartments in specific cell types, which is suggested to have relation with their specific function. GRK is directly activated by docking with active GPCRs and GRK can phosphorylate the Serine/Threonine residue on active GPCR regulating downstream signaling. Besides GPCR, GRK can also mediate the phosphorylation of non-GPCR receptors including LRP6, PDGFRb, DREAM, NFkB1 and Nedd4 and involve in specific cellular processes or cell signaling cascade (1).

Reference
1. Gurevich, E.V., Tesmer, J.J., Mushegian, A. and Gurevich, V.V. (2012) G protein-coupled receptor kinases: more than just kinases and not only for GPCRs. Pharmacol Ther, 133, 40-69. PMID: 21903131

    MASTs (Microtubule-associated Serine/Threonine-protein kinases) belong to AGC group. The MAST kinases are characterized by the presence of a Serine/Threonine kinase domain, a second 3' MAST domain and PDZ domain. The PDZ domain has been reported to mediate interaction with others proteins and help MAST to facilitate functionally important phosphorylation. The N-terminal kinase catalytic domain is relatively conserved in MAST family with a high identity (>60%). MAST family is expressed in multiple tissues. In nervous system, MAST may act as a key role through localization within the DAPC/UAPC, which is found within region of the neuromuscular junction (NMJ) and central synapses (1). Recently gene rearrangements involving MAST and Notch have been reported. Overexpression of MAST1 or MAST2 gene fusions plays an important effect on proliferative (2).

Reference
1. Garland, P., Quraishe, S., French, P. and O'Connor, V. (2008) Expression of the MAST family of serine/threonine kinases. Brain Res, 1195, 12-19. PMID: 18206861
2. Robinson, D.R., Kalyana-Sundaram, S., Wu, Y.M., Shankar, S., Cao, X., Ateeq, B., Asangani, I.A., Iyer, M., Maher, C.A., Grasso, C.S. et al. (2011) Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. Nat Med, 17, 1646-1651 PMID: 22101766

    The NDR family consists of the mammalian protein kinases NDR1 and NDR2, Drosophila melanogaster NDR, Caenorhabditis elegans SAX1, D. melanogaster and C. elegans large tumor suppressor kinases, Neurospora crassa COT1, Ustilago maydis UKC1, Saccharomyces cerevisiae Cbk1, Dbf2, and Dbf20, Schizosaccharomyces pombe Orb6 and Sid2, and several plant kinases (1). They can be found both in nucleus and cytoplasm. NDR protein kinase participates in MEKK1/2 signaling and acts as the negative regulator (2). Recently study shows that human NDR kinases can control g1/s cell cycle transition by directly regulating p21 stability (3). In addition, NDR protein kinase can be regulated through autophosphorylation and phosphorylation by an upstream kinase under a Ca2+-mediated mechanism (4).

Reference
1. Bichsel, S.J., Tamaskovic, R., Stegert, M.R. and Hemmings, B.A. (2004) Mechanism of activation of NDR (nuclear Dbf2-related) protein kinase by the hMOB1 protein. J Biol Chem, 279, 35228-35235. PMID: 15197186
2. Enomoto, A., Kido, N., Ito, M., Morita, A., Matsumoto, Y., Takamatsu, N., Hosoi, Y. and Miyagawa, K. (2008) Negative regulation of MEKK1/2 signaling by serine-threonine kinase 38 (STK38). Oncogene, 27, 1930-1938. PMID: 17906693
3. Cornils, H., Kohler, R.S., Hergovich, A. and Hemmings, B.A. (2011) Human NDR kinases control G(1)/S cell cycle transition by directly regulating p21 stability. Mol Cell Biol, 31, 1382-1395 PMID: 21262772
4. Tamaskovic, R., Bichsel, S.J., Rogniaux, H., Stegert, M.R. and Hemmings, B.A. (2003) Mechanism of Ca2+-mediated regulation of NDR protein kinase through autophosphorylation and phosphorylation by an upstream kinase. J Biol Chem, 278, 6710-6718. PMID: 12493777

    PDK1 (phosphoinositide-dependent protein kinase 1) belongs to AGC group. Two isoforms have been identified in human genome, known as PDK1 and PDK2. PDK1 now is well understood and regarded as a key regulator in varieties of cellular processes. PDK1 was first purified as an enzyme that could phosphorylate the T-loop of PKBα (Thr308) in the presence of PtdIns(3,4,5)P3. Sequence analysis shows that PDK1 consists of kinase catalytic domain in its N-terminus and a Pleckstrin homology (PH) domain at its C-terminus. PDK1 posses the high catalytic activity regulated by its intrinsic ability that phosphorylates its own T-loop residue. PDK1 is characterized by its major role in regulation of AGC kinase signal transduction. Studies show that PKB PH domain can bind 3-phosphoinositide and induce a large conformational change in PKB and the phosphorylation of PKB by PDK1 can be available. In addition, S6K and SGK are also under the regulation of PDK1 by phosphorylation (1).

Reference
1. Mora, A., Komander, D., van Aalten, D.M. and Alessi, D.R. (2004) PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol, 15, 161-170. PMID: 15209375.

    PKA (cAMP-dependent protein kinase) belongs to AGC group. PKA is characterized by its role as important downstream effecter of second messenger cAMP. PKA consists of multiple forms of regulatory and catalytic subunits and PKA holoenzyme contains two regulatory subunits and two catalytic subunits, which determines the biochemical and functional features. PKA keeps catalytically inactive under low levels of cAMP and PKA obtains its catalytic activity only after binding to the two binding sites on regulatory subunits. PKA involves in a varieties of cellular processes through phosphorylation of different nuclear and cytoplasmic substrates including metabolism, differentiation, synaptic transmission, ion channel activity, growth and development (1).

Reference
1. Feliciello, A., Gottesman, M.E. and Avvedimento, E.V. (2005) cAMP-PKA signaling to the mitochondria: protein scaffolds, mRNA and phosphatases. Cell Signal, 17, 279-287. PMID: 15567059

    PKC (protein kinase C) belongs to AGC group. PKC can be grouped into three sections based on similar structural and activation requirements: classical, novel and atypical. Classical PKCs are activated by calcium, phosphatidylserine and diacylglycerol or phorbol esters. The novel PKCs lack a conserved region found in classical PKC and is activated by different lipids. The atypical PKCs is smallest in size in all PKCs which are activated by PS. PKCs keep an inactive state in the cytosol and translocate to the membrane vesicles, nuclear structures and cytoskeletal components after cell stimulation. Activated PKCs have been shown to involve in a varieties cellular processes including receptor desensitization, transcription, immune responses and cell growth (1).

Reference
1. Keenan, C. and Kelleher, D. (1998) Protein kinase C and the cytoskeleton. Cell Signal, 10, 225-232. PMID: 9617479

    PKG (cGMP-dependent protein kinase) belongs to AGC group. Two genes have been identified in mammalian cells. The alternative splicing of the first two exons encoding the N-terminal of PKG-I cause the two isoforms, known as PKG-Iα and PKG-Iβ, PKG-Iα can be activated in a lower concentrations compared with PKG-Iβ, PKG-Iα and PKG-Iβ contain the different substrate specificity, which is meidated by the N-terminal domain. PKGs are activated downstream of cGMP signaling pathway and activated PKGs involve in a varieties of cellular processes via mediating phosphorylation of different proteins including platelet activation and adhesion, sooth muscle contraction, cardiac function and gene expressing (1).

Reference
1. Casteel, D.E., Zhang, T., Zhuang, S. and Pilz, R.B. (2008) cGMP-dependent protein kinase anchoring by IRAG regulates its nuclear translocation and transcriptional activity. Cell Signal, 20, 1392-1399. PMID: 18450420

    PKN, also known as protein kinase C related kinase, belongs to the AGC group. PKNs are Serine/Threonine protein kinases which share a C-terminal catalytic domain homologous to PKC members and a N-terminal unique regulatory region containing antiparallel coiled-coil domains (ACC domains). AGC domains act as binding interface associated with others proteins including anchoring protein CG-NAP. Between the C-terminal and N-terminal region, a C2-like region can be found in PKNs, which functions as an auto-inhibitory region. PKN localizes primarily in the cytosolic fraction and is involved in a variety of cellular processes, including cytoskeletal regulation, cell adhesion, glucose transport, regulation of meiotic maturation and embryonic cell cycles and tumorigenesis (1).

Reference
1. Mukai, H. (2003) The structure and function of PKN, a protein kinase having a catalytic domain homologous to that of PKC. J Biochem, 133, 17-27. PMID: 12761194

    RSK kinase is part of the mammalian target of rapamycin (mTOR) pathway which is a key regulator of cell growth via the regulation of protein synthesis. Both S6 kinase and eukaryotic initiation factor 4E-binding protein 1 (4EBP-1) are key mTOR effectors of cell growth. S6 kinase specifically phosphorylates ribosomal protein S6 in response to insulin or several classes of mitogens. S6 kinase is activated by Serine/Threonine phosphorylation and protein kinase C, and is inactivated by type 2A phosphatase. S6 kinase interacts with PPP1R9A/neurabin-1 (1).

Reference

1. InterPro Annotation: Ribosomal protein S6 kinase

    RSKL kinases, Ribosomal S6 kinase-like protein, belong to AGC group. At least two members have been identified in human genome (1).

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

    SGK is a type of Serine/threonine-protein kinases and belongs to AGC group. Three genes encoding SGKs have been identified, SGK1, SGK2 and SGK3. SGK1 is the most intensively studied among SGK family kinases. Studies show that SGK1 is important in activating certain potassium, sodium and chloride channels. In hepatocytes, the expression of SGK1 is stimulated by transforming growth factor-beta (TGF-beta) which is implicated in pathophysiology of diabetic complications. During osmotic stress, SGK1 can regulate the myo-inositol transporter. In addition, Deregulated expression of SGK1 has been show to be involved in cases of infertility or recurrent miscarriage in humans. Several proteins have been identified to interact with SGK, including Sodium-hydrogen exchange regulatory cofactor 2, Phosphoinositide-dependent kinase-1, Karyopherin alpha, NEDD4 and MAPK7, which is important in varieties of cellular functions (1).

Reference
1. Wikipdia Annotation: SGK