Sequential Protein Kinase C (PKC)-dependent and PKC-independent Protein Kinase D Catalytic Activation via Gq-coupled Receptors

Jácamo, Rodrigo; Sinnett‐Smith, James; Rey, Osvaldo; Waldron, Richard T.; Rozengurt, Enrique

doi:10.1074/jbc.m800442200

Cited by 84 publications

(109 citation statements)

References 85 publications

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“…PKD activation was tracked by immunoblot analysis with three different phosphorylation-site specific antibodies (PSSAs). Activation loop phosphorylation was monitored with two PSSAs that recognize phosphorylation reactions in the conserved activation loop motifs of all three PKD isoforms; recent studies indicate that the anti-PKD-Ser(P) 744 (14). PKD phosphorylation also was tracked with the anti-PKD-Ser(P) 916 PSSA that detects a conserved autophosphorylation site at the C terminus of PKD1 and PKD2, but not PKD3.…”

Section: Resultsmentioning

confidence: 99%

Protein Kinase D Isoforms Are Activated in an Agonist-specific Manner in Cardiomyocytes

Guo

Gertsberg

Özgen

et al. 2011

Journal of Biological Chemistry

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Protein kinase D (PKD) exists as a family of structurally related enzymes that are activated through similar phosphorylation-dependent mechanisms involving protein kinase C (PKC). While individual PKD isoforms could in theory mediate distinct biological functions, previous studies identify a high level of functional redundancy for PKD1 and PKD2 in various cellular contexts. This study shows that PKD1 and PKD2 are activated in a stimulus-specific manner in neonatal cardiomyocytes. The ␣ 1 -adrenergic receptor agonist norepinephrine selectively activates PKD1, thrombin and PDGF selectively activate PKD2, and endothelin-1 and PMA activate both PKD1 and PKD2. PKC activity is implicated in the ␣ 1 -adrenergic receptor pathway that activates PKD1 and the thrombin-and PDGF-dependent pathways that activate PKD2. Endothelin-1 activates PKD via both rapid PKC-dependent and more sustained PKC-independent mechanisms. The functional consequences of PKD activation were assessed by tracking phosphorylation of CREB and cardiac troponin I (cTnI), two physiologically relevant PKD substrates in cardiomyocytes. We show that overexpression of an activated PKD1-S744E/S748E transgene increases CREB-Ser 133 and cTnI-Ser 23 /Ser 24 phosphorylation, but agonist-dependent pathways that activate native PKD1 or PKD2 selectively increase CREB-Ser 133 phosphorylation; there is no associated increase in cTnI-Ser 23 /Ser 24 phosphorylation. Gene silencing studies provide unanticipated evidence that PKD1 down-regulation leads to a compensatory increase in PKD2 activity and that down-regulation of PKD1 (alone or in combination with PKD2) leads to an increase in CREB-Ser 133 phosphorylation. Collectively, these studies identify distinct roles for native PKD1 and PKD2 enzymes in stress-dependent pathways that influence cardiac remodeling and the progression of heart failure. Protein kinase D (PKD)2 consists of a family of three structurally related serine-threonine kinases (termed PKD1 (or PKD), PKD2 and PKD3 (or PKD)) that play key roles in cell growth, differentiation, migration, and apoptosis (1). PKD isoforms share a common domain structure, consisting of a C-terminal kinase domain and an N-terminal regulatory domain. The regulatory domain contains a C1 domain that anchors full-length PKD to diacylglycerol/phorbol ester-containing membranes and a pleckstrin homology (PH) domain that participates in intramolecular autoinhibitory interactions. PKD activation is generally attributed to a phosphorylation-dependent mechanism involving PKC. Receptors that activate phospholipase C and promote diacyglycerol accumulation co-localize PKD with allosterically activated PKC at lipid membranes. PKD is then activated as a result of phosphorylation at Ser 744 and Ser 748 , a pair of highly conserved serine residues in the activation loop of the kinase domain (nomenclature based upon rodent PKD1). Once activated, PKD1 and PKD2 execute autophosphorylation reactions at a serine residue in a PKD consensus phosphorylation motif at the extreme C terminus (Ser 916 in...

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Section: Resultsmentioning

confidence: 99%

Protein Kinase D Isoforms Are Activated in an Agonist-specific Manner in Cardiomyocytes

Guo

Gertsberg

Özgen

et al. 2011

Journal of Biological Chemistry

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“…Phosphorylation of PKD by novel PKCs in the activation loop is generally considered as a prerequisite for activation. However, a PKC-independent role for PKD3 has been suggested in basal glucose uptake of skeletal muscle cells (35) and more recent studies demonstrated that the rapid PKC-dependent PKD activation is followed by a sustained, PKC-independent phase of catalytic activation (36).…”

Section: Discussionmentioning

confidence: 99%

GIT1 Phosphorylation on Serine 46 by PKD3 Regulates Paxillin Trafficking and Cellular Protrusive Activity

Huck

Kemkemer

Franz‐Wachtel

et al. 2012

Journal of Biological Chemistry

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Background:The multidomain protein GIT1 is involved in cytoskeletal rearrangements and cell motility. Results: GIT1 phosphorylation on serine 46 by PKD3 regulates localization of GIT1-paxillin complexes. Conclusion: Paxillin trafficking and cellular protrusive activity are controlled by GIT1 serine 46 phosphorylation. Significance: Selective phosphorylation of GIT1 by PKD3 implicates a specific function for this PKD isoform in the regulation of cell shape and motility.

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“…PKD1 catalytic activation within cells leads to its auto-phosphorylation at Ser 916 and Ser 748 (33)(34)(35)(36). Rapid PKC-dependent PKD1 activation is followed by a late PKC-independent phase of activation induced by GPCR agonists (35)(36)(37). Accumulating evidence demonstrates that the PKD family plays an important role in a variety of cellular processes and activities, including cytoskeletal organization, gene expression, cell migration, and proliferation (19).…”

mentioning

confidence: 99%

“…In intestinal epithelial cells, PKD1 activation mediates migration and proliferation both in vitro and in vivo (36,38). Accordingly, multiple growth-promoting stimuli rapidly activate PKD1 catalytic activity in intestinal epithelial cells (23, 36, 38 -40) through activation loop phosphorylation (30,(35)(36)(37). Furthermore, transgenic mice that express elevated PKD1 protein in intestinal epithelial cells display a marked increase in DNA-synthesizing cells in their intestinal crypts and a significant increase in the length and total number of cells per crypt (36).…”

mentioning

confidence: 99%

Biphasic Regulation of Yes-associated Protein (YAP) Cellular Localization, Phosphorylation, and Activity by G Protein-coupled Receptor Agonists in Intestinal Epithelial Cells

Wang¹,

Sinnett‐Smith

Stevens³

et al. 2016

Journal of Biological Chemistry

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Sequential Protein Kinase C (PKC)-dependent and PKC-independent Protein Kinase D Catalytic Activation via Gq-coupled Receptors

Cited by 84 publications

References 85 publications

Protein Kinase D Isoforms Are Activated in an Agonist-specific Manner in Cardiomyocytes

Protein Kinase D Isoforms Are Activated in an Agonist-specific Manner in Cardiomyocytes

GIT1 Phosphorylation on Serine 46 by PKD3 Regulates Paxillin Trafficking and Cellular Protrusive Activity

Biphasic Regulation of Yes-associated Protein (YAP) Cellular Localization, Phosphorylation, and Activity by G Protein-coupled Receptor Agonists in Intestinal Epithelial Cells

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