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    bullet point  PKD IMAP TR-FRET APAC Document
     
     
    Diacylglycerol (DAG) is (1) a key second messenger in cells and (2) generated upon G-protein-coupled and tyrosine kinase receptor engagement/activation. There are currently six classes/families of DAG receptors: (1) Protein kinase C (PKC); (2) the chimerin Rac GTPase-activating proteins; (3) the Ras guanyl-nucleotide-releasing proteins (Ras GRPs); (4) Munc13s; (5) the DAG kinases (DGKs); and (6) Protein kinase D (PKD).
    There are four members within the PKD family: PKD1 (murine PKD, human PKCμ), PKD2 and PKD3 (PKDν). Although originally classified as an atypical isoform of the PKC, PKD/PKCμ actually belongs to a subfamily of serine/threonine kinases within the Ca2+/calmodulin-dependent kinase (CaMK) superfamily (see Wang 2006 for review). This is based primarily on the fact that PKD/PKCμ shares the highest sequence homology within its catalytic domain with myosin light chain kinase and CAMKs (Valverde et al., 1994). Interestingly, PKD/PKCμ serves as both a DAG receptor and a substrate for PKC (reviewed in Wang 2006). In an unactivated state, PKD/PKCμ is primarily localized in the cytosol; however, activated PKD/PKCμ is mobile and can move between different subcellular compartments. This ability of PKD/PKCμ to localize to different subcellular compartments suggests that the (1) localization of PKD/PKCμ at different sites results in different physiological functional roles; (2) shuttling of PKD/PKCμ between multiple subcellular compartments facilitates the transmission of signals between those compartments; and (3) migration of PKD/PKCμ between multiple subcellular compartments can localize PKD/PKCμ to different substrates, reminiscent of the localization of Polo-like kinase I to multiple mitotic structures during the cell cycle (reviewed in Wang, 2006; Marklund et al., 2003; Baron and Malhotra, 2002).
    There is considerable evidence emerging that PKD/PKCμ regulates a variety of physiological processes including signal transduction, membrane trafficking, cell survival, cell migration, cell differentiation and cell proliferation (Rozengurt et al., 2005; Wang 2006). As described in Wang et al. (2006), there is accumulating evidence that PKD/PKCμ may be a focus of future drug design efforts and the rationale is as follows:
    PKD/PKCμ lies at a significant juncture of DAG-PKC signaling pathways which is often unregulated in cancer and other disease states
    PKD/PKCμ is involved in DNA damage, cell growth, differentiation, survival, migration and invasion
    PKD/PKCμ regulates the function of class IIa HDACs, which are drug targets of several disease states including cardiomyopathy, osteodystrophy, neurodegenerative disorders and cancer
    PKD/PKCμ is involved in oxidative stress response, which may be involved with malignant transformation and aging
     
    Documents
  • PKD IMAP FP APAC Document
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