Regulation and Function of Protein Kinase D Signaling

Abstract

AbstractProtein kinase D (PKD) is an evolutionarily conserved protein kinase with structural, enzymological, and regulatory properties different from the PKC family members. The most distinct characteristics of PKD are the presence of a catalytic domain distantly related to Ca2+-regulated kinases and a pleckstrin homology (PH) domain that regulates enzyme activity. The N-terminal region of PKD also contains a tandem repeat of cysteine-rich, zinc finger-like motifs which confer high affinity binding of phorbol esters and repress catalytic kinase activity. The subsequent identification of PKD2 and PKD3, similar in overall structure and amino acid sequence to PKD, confirmed the notion that PKD is the founding member of a new family of protein kinases, now classified in the mammalian kinome within the Ca2+/calmodulin-dependent protein kinase (CaMK) group. PKD can be activated within intact cells by multiple stimuli acting through receptor-mediated pathways. Rapid PKD activation has been demonstrated in response to G protein-coupled receptor agonists, growth factors, cross-linking of B-cell receptor and T-cell receptor and cellular stress. The phosphorylation of Ser744 and Ser748 in the activation loop of PKD is critical for its activation. Rapid PKC-dependent PKD activation can be followed by a late, PKC-independent, phase of catalytic activation and phosphorylation induced by agonists of Gq-coupled receptors. Accumulating evidence suggest that PKD plays a role in multiple cellular processes and activities, including signal transduction, chromatin organization, Golgi function, gene expression, immune regulation, cardiac hypertrophy and cell survival, adhesion, motility, polarity, DNA synthesis and proliferation. The studies on regulation and function of PKD reviewed here illustrate a remarkable diversity in both its signal generation and distribution and its potential for complex regulatory interactions with multiple downstream pathways. In conclusion, PKD emerges as a key node in cellular signal transduction.KeywordsProtein kinase CG protein-coupled receptorsPhorbol estersSignal transductionIntracellular translocationCell proliferation