Phosphorylation-dependent protein kinase Dactivation

Waldron, Richard T.; Iglesias, Teresa; Rozengurt, Enrique

doi:10.1002/(sici)1522-2683(19990201)20:2<382::aid-elps382>3.0.co;2-n

Cited by 60 publications

(62 citation statements)

References 52 publications

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“…PKD can be activated by a variety of stimuli including biologically active phorbol esters, growth factors, and T-and B-cell receptor agonists via PKC-dependent pathways (6,7). PKD activation appears to involve the phosphorylation of Ser-744 and Ser-748 within the activation loop of the catalytic domain as well as the autophosphorylation of Ser-916 (6).…”

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confidence: 99%

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Thrombin Rapidly Induces Protein Kinase D Phosphorylation, and Protein Kinase C δ Mediates the Activation

Tan¹,

Xu²,

Ohba³

et al. 2003

Journal of Biological Chemistry

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Thrombin plays a critical role in hemostasis, thrombosis, and inflammation. However, the responsible intracellular signaling pathways triggered by thrombin are still not well defined. We report here that thrombin rapidly and transiently induces activation of protein kinase D (PKD) in aortic smooth muscle cells. Our data demonstrate that protein kinase C (PKC) inhibitors completely block thrombin-induced PKD activation, suggesting that thrombin induces PKD activation via a PKC-dependent pathway. Furthermore, our results show that thrombin rapidly induces PKC␦ phosphorylation and that the PKC␦-specific inhibitor rottlerin blocks thrombin-induced PKD activation, suggesting that PKC␦ mediates the thrombin-induced PKD activation. Using dominant negative approaches, we demonstrated that expression of a dominant negative PKC␦ inhibits the phosphorylation and activation of PKD induced by thrombin, whereas neither PKC⑀ nor PKC affects thrombin-induced PKD activation. In addition, our results of co-immunoprecipitation assays showed that PKD forms a complex with PKC␦ in smooth muscle cells. Taken together, the findings of the present study demonstrate that thrombin induces activation of PKD and reveal a novel role of PKC␦ in mediating thrombininduced PKD activation in vascular smooth muscle cells.Thrombin belongs to the multifunctional serine protease family and plays an important role in the blood coagulation cascade through the cleavage of fibrinogen to fibrin (1, 2). Thrombin also exerts direct effects on cells to regulate platelet aggregation, endothelial cell activation, and smooth muscle cell (SMC) 1 proliferation via interactions with members of the protease-activated receptor (PAR) family, such as PAR1, PAR2, PAR3, and PAR4, known as G-protein-coupled receptors (2, 3). However, the intracellular signaling cascades downstream from the thrombin receptors are surprisingly complex and are still not well understood.Protein kinase D (PKD), also known as protein kinase C (4, 5), is a newly described serine/threonine protein kinase with unique structural, enzymological, and regulatory properties that are different from those of the PKC family members. The most distinct characteristics of PKD are the presence of a catalytic domain distantly related to Ca 2ϩ -regulated kinases, a pleckstrin homology domain within the regulatory region, and a highly hydrophobic stretch of amino acids in its N-terminal region (6, 7).PKD can be activated by a variety of stimuli including biologically active phorbol esters, growth factors, and T-and B-cell receptor agonists via PKC-dependent pathways (6,7). PKD activation appears to involve the phosphorylation of Ser-744 and Ser-748 within the activation loop of the catalytic domain as well as the autophosphorylation of Ser-916 (6). PKD has been implicated in the regulation of a variety of cellular functions including NF B-mediated gene expression, Na ϩ /H ϩ antiport activity, Golgi organization and function, and protein transport (7,8). The aim of the present study is to determine whether and h...

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confidence: 99%

“…The most distinct characteristics of PKD are the presence of a catalytic domain distantly related to Ca 2ϩ -regulated kinases, a pleckstrin homology domain within the regulatory region, and a highly hydrophobic stretch of amino acids in its N-terminal region (6,7).…”

mentioning

confidence: 99%

Thrombin Rapidly Induces Protein Kinase D Phosphorylation, and Protein Kinase C δ Mediates the Activation

Tan¹,

Xu²,

Ohba³

et al. 2003

Journal of Biological Chemistry

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“…However, PKDs are structurally and catalytically distinct to PKCs with different substrate specificities and modes of regulation (2,3,11). In fact, the relationship between PKCs and PKD1 is a regulatory one, as in a variety of cell lineages stimulation of PKCs is necessary for PKD activation (6,12,13). The role of PKCs in PKD1 activation is explained by their ability to phosphorylate serines 744 and 748 within the PKD1 catalytic domain (13,14).…”

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confidence: 99%

“…In fact, the relationship between PKCs and PKD1 is a regulatory one, as in a variety of cell lineages stimulation of PKCs is necessary for PKD activation (6,12,13). The role of PKCs in PKD1 activation is explained by their ability to phosphorylate serines 744 and 748 within the PKD1 catalytic domain (13,14). The phosphorylation of Ser-744 and Ser-748 is crucial for PKD1 activation in epithelial cells as substitution of these residues with alanines creates a catalytically dead kinase (15).…”

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confidence: 99%

“…It is proposed that the PKD N terminus maintains the molecule in an inactive conformation, which is relieved by phosphorylation of Ser-744 and Ser-748 by PKCs (14,19). In this minimal model the phosphorylation of Ser-744/Ser-748 is sufficient for PKD1 stimulation (13,20,21). One basis for this conclusion is that a PKD1 mutant with glutamic residues substituted at positions 744 and 748 as phospho-mimics (PKD-S744E/S748E) is constitutively active in Cos7 and HeLa cells.…”

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Dual Phospholipase C/Diacylglycerol Requirement for Protein Kinase D1 Activation in Lymphocytes

Wood

Marklund

Cantrell

2005

Journal of Biological Chemistry

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The serine/threonine kinase protein kinase D1 (PKD1) is a protein kinase C (PKC) substrate that mediates antigen receptor signal transduction in lymphocytes. PKC phosphorylates serines 744/748 within the PKD1 catalytic domain, and this is proposed to be necessary and sufficient for enzyme activation. Hence, a PKD1 mutant with alanine substituted at positions 744 and 748 (PKD-S744A/S748A) is catalytically inactive. Conversely, a PKD1 mutant with glutamic residues substituted at positions 744 and 748 as phospho-mimics (PKD-S744E/ S748E) is constitutively active when expressed in Cos7 or HeLa cells. The present study reveals that Ser-744/ Ser-748 phosphorylation is required for PKD1 activation in lymphocytes. However, PKD-S744E/S748E is not constitutively active but, like the wild type enzyme, requires antigen receptor triggering or phorbol ester stimulation. Antigen receptor activation of wild type PKD is dependent on phospholipase C (PLC)/diacylglycerol (DAG) and PKC, whereas PKD-S744E/S748E is only dependent on PLC/DAG but no longer requires PKC. Hence, substitution of serines 744 and 748 with glutamic residues as phospho-mimics bypasses the PKC requirement for PKD1 activation but does not bypass the need for antigen receptors, PLC, or DAG. In lymphocytes, PKD1 is, thus, not regulated by PLC and PKC in a linear pathway; rather, PKD1 activation has more stringent requirements for integration of dual PLC signals, one mediated by PKCs and one that is PKC-independent.

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Loss of cell–cell contacts induces NF‐κB via RhoA‐mediated activation of protein kinase D1

Cowell

Yan

Eiseler

et al. 2009

J of Cellular Biochemistry

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Cell–cell contacts mediated by cadherins are known to inhibit the small Rho-GTPase RhoA. We here show that in epithelial cells the disruption of these cell–cell contacts as mediated by a calcium switch leads to actin re-organization and the activation of RhoA. We identified the serine/threonine kinase protein kinase D1 (PKD1) as a downstream target for RhoA in this pathway. After disruption of cell–cell contacts, PKD1 relayed RhoA activation to the induction of the transcription factor NF-κB. We found that a signaling complex composed of the kinases ROCK, novel protein kinase C (nPKC), and Src family kinases (SFKs) is upstream of PKD1 and crucial for RhoA-mediated NF-κB activation. In conclusion, our data suggest a previously undescribed signaling pathway of how RhoA is activated by loss of cell–cell adhesions and by which it mediates the activation of NF-κB. We propose that this pathway is of relevance for epithelial tumor cell biology, where loss of cell–cell contacts has been implicated in regulating cell survival and motility.

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Phosphorylation-dependent protein kinase Dactivation

Cited by 60 publications

References 52 publications

Thrombin Rapidly Induces Protein Kinase D Phosphorylation, and Protein Kinase C δ Mediates the Activation

Thrombin Rapidly Induces Protein Kinase D Phosphorylation, and Protein Kinase C δ Mediates the Activation

Dual Phospholipase C/Diacylglycerol Requirement for Protein Kinase D1 Activation in Lymphocytes

Loss of cell–cell contacts induces NF‐κB via RhoA‐mediated activation of protein kinase D1

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