Protein Kinase D Signaling (2005)

A rapid increase in the synthesis of lipid-derived second messengers with subsequent activation of protein phosphorylation cascades has emerged as one of the fundamental mechanisms of signal transduction in animal cells. A plethora of external signals, including hormones, neurotransmitters, growth factors, cytokines, bioactive lipids, and tastants promote the stimulation of the isoforms of the PLC 1The abbreviations used are: PLC, phospholipase C; DAG, diacylglycerol; PKC, protein kinase C; PKD, protein kinase D; CRD, cysteinerich domain; PH, pleckstrin homology; GPCR, G protein-coupled receptor; CAMK, Ca2+/calmodulin-dependent protein kinase; JNK, c-Jun NH2-terminal kinase; ERK, extracellular signal-regulated kinase. 1The abbreviations used are: PLC, phospholipase C; DAG, diacylglycerol; PKC, protein kinase C; PKD, protein kinase D; CRD, cysteinerich domain; PH, pleckstrin homology; GPCR, G protein-coupled receptor; CAMK, Ca2+/calmodulin-dependent protein kinase; JNK, c-Jun NH2-terminal kinase; ERK, extracellular signal-regulated kinase. family, including β, γ, δ, and ϵ. PLCs catalyze the hydrolysis of phosphatidylinositol 4,5-bisphosphate to produce two second messengers: inositol 1,4,5-P3, which triggers the release of Ca2+ from internal stores, and DAG, which elicits cellular responses through a variety of effectors (1.Brose N. Betz A. Wegmeyer H. Curr. Opin. Neurobiol. 2004; 14: 328-340Crossref PubMed Scopus (102) Google Scholar). The most prominent intracellular targets of DAG are the classic (α, β, γ) and novel (δ, ϵ, η, θ) isoforms of PKC, which are differentially expressed in cells and tissues (2.Newton A.C. Curr. Opin. Cell Biol. 1997; 9: 161-167Crossref PubMed Scopus (843) Google Scholar, 3.Mellor H. Parker P.J. Biochem. J. 1998; 332: 281-292Crossref PubMed Scopus (1345) Google Scholar). The mechanisms by which PKC-mediated signals are propagated to critical downstream targets remain incompletely understood. Protein kinase D (PKD), the founding member of a new family of serine/threonine protein kinases and the subject of this minireview, occupies a unique position in the signal transduction pathways initiated by DAG and PKC. PKD not only is a direct DAG target but also lies downstream of PKCs in a novel signal transduction pathway implicated in the regulation of multiple fundamental biological processes. Complementary DNA clones encoding human PKD (initially called atypical PKCμ) and PKD from mouse were identified by two different laboratories in 1994 (4.Johannes F.J. Prestle J. Eis S. Oberhagemann P. Pfizenmaier K. J. Biol. Chem. 1994; 269: 6140-6148Abstract Full Text PDF PubMed Google Scholar, 5.Valverde A.M. Sinnett-Smith J. Van Lint J. Rozengurt E. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 8572-8576Crossref PubMed Scopus (356) Google Scholar). Subsequently, two additional mammalian protein kinases have been identified that share extensive overall homology with PKD (Fig. 1), termed PKD2 (6.Sturany S. Van Lint J. Mueller F. Wilda M. Hameister H. Hoecker M. Brey A. Gern U. Vandenheede J. Gress T. Adler G. Seufferlein T. J. Biol. Chem. 2001; 276: 3310-3318Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar) and PKCν/PKD3 (7.Hayashi A. Seki N. Hattori A. Kozuma S. Saito T. Biochim. Biophys. Acta. 1999; 1450: 99-106Crossref PubMed Scopus (171) Google Scholar, 8.Rey O. Yuan J. Young S.H. Rozengurt E. J. Biol. Chem. 2003; 278: 23773-23785Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). The N-terminal regulatory portion of PKD (Fig. 1) contains a tandem repeat of zinc finger-like cysteine-rich motifs (termed the cysteine-rich domain or CRD) highly homologous to domains found in DAG/phorbol ester-sensitive PKCs and in other signaling proteins regulated by DAG, including chimerins, Ras-GRP, Munc13, and DAG kinases (see Ref. 1.Brose N. Betz A. Wegmeyer H. Curr. Opin. Neurobiol. 2004; 14: 328-340Crossref PubMed Scopus (102) Google Scholar for review). Accordingly, PKD binds phorbol esters with high affinity via its CRD (5.Valverde A.M. Sinnett-Smith J. Van Lint J. Rozengurt E. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 8572-8576Crossref PubMed Scopus (356) Google Scholar, 9.Van Lint J.V. Sinnett-Smith J. Rozengurt E. J. Biol. Chem. 1995; 270: 1455-1461Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 10.Wang Q.J. Fang T.W. Yang D. Lewin N.E. Van Lint J. Marquez V.E. Blumberg P.M. Mol. Pharmacol. 2003; 64: 1342-1348Crossref PubMed Scopus (21) Google Scholar). The individual cysteine-rich motifs of the CRD, referred to as cys1 and cys2 (Fig. 1), are functionally dissimilar with the cys2 motif responsible for the majority of high affinity [3H]phorbol 12,13-dibutyrate binding both in vivo and in vitro (11.Iglesias T. Matthews S. Rozengurt E. FEBS Lett. 1998; 437: 19-23Crossref PubMed Scopus (60) Google Scholar, 12.Rey O. Rozengurt E. Biochem. Biophys. Res. Commun. 2001; 287: 21-26Crossref PubMed Scopus (28) Google Scholar). As described below, the CRD plays a critical role in mediating PKD translocation to the plasma membrane and nucleus in cells challenged with a variety of stimuli and also represses the catalytic activity of the enzyme (13.Iglesias T. Rozengurt E. FEBS Lett. 1999; 454: 53-56Crossref PubMed Scopus (45) Google Scholar). Interposed between the CRD and the catalytic domain, PKD also contains a PH domain (14.Iglesias T. Rozengurt E. J. Biol. Chem. 1998; 273: 410-416Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). Found in many signal transduction proteins, PH domains bind to membrane lipids as well as to other proteins (reviewed in Ref. 15.Cozier G.E. Carlton J. Bouyoucef D. Cullen P.J. Curr. Top. Microbiol. Immunol. 2004; 282: 49-88PubMed Google Scholar). PH domains have also been determined to play an autoregulatory role in some protein kinases, including PKD. Thus, PKD mutants with deletions or with single amino acid substitutions within the PH domain are fully active (14.Iglesias T. Rozengurt E. J. Biol. Chem. 1998; 273: 410-416Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 16.Waldron R.T. Iglesias T. Rozengurt E. J. Biol. Chem. 1999; 274: 9224-9230Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar), indicating that the PH domain, like the CRD, helps to maintain PKD in an inactive catalytic state. The initial description of PKD as an atypical isoform of PKC (4.Johannes F.J. Prestle J. Eis S. Oberhagemann P. Pfizenmaier K. J. Biol. Chem. 1994; 269: 6140-6148Abstract Full Text PDF PubMed Google Scholar) and the inclusion of PKD/PKCμ in reviews concerning the PKC family, which belongs to the AGC group (named for PKA, PKG, and PKC) (2.Newton A.C. Curr. Opin. Cell Biol. 1997; 9: 161-167Crossref PubMed Scopus (843) Google Scholar, 3.Mellor H. Parker P.J. Biochem. J. 1998; 332: 281-292Crossref PubMed Scopus (1345) Google Scholar), contributed to a perception that PKD belongs to the PKC family. However, it was noted from the outset that the catalytic domain of PKD has highest sequence homology with myosin light chain kinase and CAMKs (5.Valverde A.M. Sinnett-Smith J. Van Lint J. Rozengurt E. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 8572-8576Crossref PubMed Scopus (356) Google Scholar). Indeed, the three isoforms of PKD are now classified as a new protein kinase family within the CAMK group, separate from the AGC group (17.Hanks S.K. Genome Biol. 2003; 4: 111Crossref PubMed Scopus (206) Google Scholar). This scheme reflects the notion that the evolutionary relationship between protein kinases is most appropriately linked to their respective catalytic domain structures. Full-length PKD isolated from multiple cell types or tissues exhibits very low catalytic activity (9.Van Lint J.V. Sinnett-Smith J. Rozengurt E. J. Biol. Chem. 1995; 270: 1455-1461Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar) that can be stimulated by phosphatidylserine micelles and either DAG or phorbol esters (9.Van Lint J.V. Sinnett-Smith J. Rozengurt E. J. Biol. Chem. 1995; 270: 1455-1461Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 18.Johannes F.J. Prestle J. Dieterich S. Oberhagemann P. Link G. Pfizenmaier K. Eur. J. Biochem. 1995; 227: 303-307Crossref PubMed Scopus (95) Google Scholar, 19.Matthews S.A. Pettit G.R. Rozengurt E. J. Biol. Chem. 1997; 272: 20245-20250Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). These early studies demonstrated that PKD is a phospholipid/DAG-stimulated serine/threonine protein kinase and implied that PKD represents a novel component of the signal transduction initiated by DAG production in their target cells (20.Rozengurt E. Sinnett-Smith J. Zugaza J.L. Biochem. Soc. Trans. 1997; 25: 565-571Crossref PubMed Scopus (59) Google Scholar). Subsequent studies, which aimed to define the regulatory properties of PKD within intact cells, produced multiple lines of evidence that elucidated a mechanism of PKD activation distinct from the direct stimulation of enzyme activity by DAG/phorbol ester plus phospholipids obtained in vitro. Treatment of intact cells with phorbol esters, cell-permeant DAGs, or bryostatin induced a dramatic conversion of PKD from an inactive to an active form, as shown by in vitro kinase assays performed in the absence of lipid co-activators (19.Matthews S.A. Pettit G.R. Rozengurt E. J. Biol. Chem. 1997; 272: 20245-20250Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 21.Zugaza J.L. Sinnett-Smith J. Van Lint J. Rozengurt E. EMBO J. 1996; 15: 6220-6230Crossref PubMed Scopus (220) Google Scholar). In all these cases, PKD activation was selectively and potently blocked by cell treatment with PKC inhibitors (e.g. GFI and Ro 31–8220) that did not directly inhibit PKD catalytic activity (19.Matthews S.A. Pettit G.R. Rozengurt E. J. Biol. Chem. 1997; 272: 20245-20250Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 21.Zugaza J.L. Sinnett-Smith J. Van Lint J. Rozengurt E. EMBO J. 1996; 15: 6220-6230Crossref PubMed Scopus (220) Google Scholar), suggesting that PKD activation in intact cells is mediated, directly or indirectly, through PKCs. In line with this conclusion, cotransfection of PKD with active mutant forms of “novel” PKCs (PKCs δ, ϵ, η, θ) resulted in robust PKD activation in the absence of cell stimulation (16.Waldron R.T. Iglesias T. Rozengurt E. J. Biol. Chem. 1999; 274: 9224-9230Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 21.Zugaza J.L. Sinnett-Smith J. Van Lint J. Rozengurt E. EMBO J. 1996; 15: 6220-6230Crossref PubMed Scopus (220) Google Scholar, 22.Yuan J.Z. Bae D. Cantrell D. Nel A.E. Rozengurt E. Biochem. Biophys. Res. Commun. 2002; 291: 444-452Crossref PubMed Scopus (60) Google Scholar, 23.Storz P. Doppler H. Toker A. Mol. Cell. Biol. 2004; 24: 2614-2626Crossref PubMed Scopus (200) Google Scholar). A variety of regulatory peptides, including bombesin, bradykinin, endothelin, and vasopressin, or growth factors (e.g. platelet-derived growth factor) also induced PKD activation via a PKC-dependent pathway in intact fibroblasts (24.Zugaza J.L. Waldron R.T. Sinnett-Smith J. Rozengurt E. J. Biol. Chem. 1997; 272: 23952-23960Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). These results provided the first evidence indicating the operation of a PKC/PKD signaling cascade in response to receptor-activated pathways. Subsequently, the functioning of PKC-dependent PKD activation has been extended to and further explored in many normal cell types, including fibroblasts (19.Matthews S.A. Pettit G.R. Rozengurt E. J. Biol. Chem. 1997; 272: 20245-20250Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 25.Chiu T. Rozengurt E. FEBS Lett. 2001; 489: 101-106Crossref PubMed Scopus (21) Google Scholar, 26.Zhukova E. Sinnett-Smith J. Rozengurt E. J. Biol. 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Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). A critical in the regulation of protein kinases that in signaling cascades is the phosphorylation of within the kinase catalytic domain, in a the highly kinase and kinase termed the or of and mutant forms of PKD, two in the PKD activation and in mouse PKD (Fig. 1), were identified T. Waldron R.T. Rozengurt E. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus (154) Google Scholar, R.T. Iglesias T. Rozengurt E. 1999; PubMed Scopus Google Scholar). a PKD mutant with and to was to activation in response to cell of both to acid a active PKD. mutants in which acid or produced The properties of these mutant forms of PKD were with a role of and in an that PKD and a second that PKD PKD activation phosphorylation was demonstrated in response to regulatory peptides, of G proteins, and in many cell types E. Sinnett-Smith J. Rozengurt E. J. Biol. 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Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, T. Waldron R.T. Rozengurt E. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus (154) Google Scholar) and R.T. O. Zhukova E. Rozengurt E. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, P. Toker A. EMBO J. 2003; PubMed Scopus Google Scholar) is to play a role in PKD it is that PKD phosphorylation and is by a of stimuli in multiple cell studies in vitro and in vivo further the role of as an kinase in the activation phosphorylation of PKD. in the of phorbol and intact PKD In of to the induced rapid and with a increase in PKD catalytic activity R.T. Rozengurt E. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). of in intact cells activation phosphorylation induced by stimulation O. Reeve Jr., J.R. Zhukova E. Sinnett-Smith J. Rozengurt E. J. Biol. Chem. 2004; 279: 34361-34372Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). these studies the notion that novel PKCs directly PKD by activation phosphorylation and PKD is in the of cells (27.Rey O. Young S.H. Cantrell D. Rozengurt E. J. Biol. Chem. 2001; 276: 32616-32626Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, S.A. Iglesias T. Rozengurt E. Cantrell D. EMBO J. PubMed Scopus Google Scholar, S. Iglesias T. Cantrell D. Rozengurt E. FEBS Lett. 1999; PubMed Scopus Google Scholar, O. Sinnett-Smith J. Zhukova E. Rozengurt E. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar) and to a in intracellular including and M. A. I. Van Lint J. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, A. Link G. A. S. Pfizenmaier K. F.J. J. Cell Biol. 2002; PubMed Scopus Google Scholar) but from the to different in response to activation (27.Rey O. Young S.H. Cantrell D. Rozengurt E. J. Biol. Chem. 2001; 276: 32616-32626Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, S.A. Iglesias T. Rozengurt E. Cantrell D. EMBO J. PubMed Scopus Google Scholar, S. Iglesias T. Cantrell D. Rozengurt E. FEBS Lett. 1999; PubMed Scopus Google Scholar, O. Sinnett-Smith J. Zhukova E. Rozengurt E. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, O. Zhukova E. Sinnett-Smith J. Rozengurt E. J. Cell. Physiol. 2003; PubMed Scopus Google Scholar). translocation is with a PKD domain and rapid and (Fig. The first of PKD translocation is by the cys2 motif of the CRD, which binds to DAG produced the of the plasma membrane as a of PLC stimulation (27.Rey O. Young S.H. Cantrell D. Rozengurt E. J. Biol. Chem. 2001; 276: 32616-32626Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). has also been that cys2 and can directly bind to E. A. Cell. 2003; 4: Full Text Full Text PDF PubMed Scopus Google Scholar). In the cys1 PKD to the Van Lint J. EMBO J. 2001; PubMed Scopus Google Scholar). The second translocation from the plasma membrane to the the PKC-dependent phosphorylation of PKD activation and (27.Rey O. Young S.H. Cantrell D. Rozengurt E. J. Biol. Chem. 2001; 276: 32616-32626Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). PKD is via its cys2 the it to the through a pathway that the PH domain of PKD O. Sinnett-Smith J. Zhukova E. Rozengurt E. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). of cells and cells rapid translocation of PKD from the to the plasma membrane S.A. Iglesias T. Rozengurt E. Cantrell D. EMBO J. PubMed Scopus Google Scholar, S. Iglesias T. Cantrell D. Rozengurt E. FEBS Lett. 1999; PubMed Scopus Google Scholar). The plasma membrane translocation by is and not to the S.A. Iglesias T. Rozengurt E. Cantrell D. EMBO J. PubMed Scopus Google Scholar). These different the notion that in to the in PKD, other factors including cell and proteins also its intracellular In this the protein kinase A protein which activity and is linked to forms a that PKD, and that PKD translocation and activation G. Mol. Cell. 2004; 15: Full Text Full Text PDF PubMed Scopus Google Scholar). results also demonstrated that and promote PKD activation J. J. Rozengurt E. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Rozengurt E. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). These the notion that both and pathways to PKD translocation and activation in their target cells. PKD2 also translocation from the to the plasma membrane in response to stimulation O. Yuan J. Rozengurt E. Biochem. Biophys. Res. Commun. 2003; PubMed Scopus Google Scholar). The translocation of PKD2 PKC activity as in the of PKD, can be by the translocation of O. Reeve Jr., J.R. Zhukova E. Sinnett-Smith J. Rozengurt E. J. Biol. Chem. 2004; 279: 34361-34372Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). In to PKD, active PKD2 in the its plasma membrane either PKD or is in the nucleus as well as the of cells O. Yuan J. Young S.H. Rozengurt E. J. Biol. Chem. 2003; 278: 23773-23785Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). including (e.g. and cell a rapid and plasma membrane translocation of O. Yuan J. Young S.H. Rozengurt E. J. Biol. Chem. 2003; 278: 23773-23785Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, S.A. A.M. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). to PKD, but not activation the of the nucleus O. Yuan J. Young S.H. Rozengurt E. J. Biol. Chem. 2003; 278: 23773-23785Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). The in the intracellular of the different PKD the to multiple distinct The studies a of PKD activation in response to rapid of DAG in the plasma membrane that the and in PKD with PKD catalytic activity and phosphorylation O. Yuan J. Young S.H. Rozengurt E. J. Biol. Chem. 2003; 278: 23773-23785Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 30.Rey O. Reeve Jr., J.R. Zhukova E. Sinnett-Smith J. Rozengurt E. J. Biol. Chem. 2004; 279: 34361-34372Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, R.T. O. Zhukova E. Rozengurt E. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, R.T. O. Iglesias T. T. Cantrell D. Rozengurt E. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, R.T. Rozengurt E. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, O. Sinnett-Smith J. Zhukova E. Rozengurt E. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). The of this in are as 1) In cells, PKD is in a of very low kinase catalytic activity through by the CRD and PH In these cells, the of PKD results from in which the of that of of DAG PKD translocation from the to the plasma membrane novel PKCs are also in response to DAG by DAG, PKD and the activation of this enzyme in an active The and PKD from the plasma to the and the Thus, PKCs PKD activation by phosphorylation of and with rapid of PKD from the plasma membrane to signals initiated the cell the of the including the results that a the regulation of the catalytic activity and intracellular of PKD2 and in response to DAG In the of this the of inactive PKD, and in the and nucleus results from their respective of and O. Yuan J. Young S.H. Rozengurt E. J. Biol. Chem. 2003; 278: 23773-23785Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, O. Sinnett-Smith J. Zhukova E. Rozengurt E. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, O. Yuan J. Rozengurt E. Biochem. Biophys. Res. Commun. 2003; PubMed Scopus Google Scholar). as and in for PKD, production of DAG in the plasma membrane also triggers in and catalytic activation of PKD2 and In this a mechanism of PKD family activation can responses the of The of activation shown in that the are well to and Indeed, it is that the are implicated in the regulation of a of fundamental biological including signal membrane and cell and PKD the of the and activation and c-Jun phosphorylation in response to growth activation M. A. A. EMBO J. 1999; PubMed Scopus Google Scholar, C. Rozengurt E. Biochem. Biophys. Res. Commun. 2001; 282: PubMed Scopus Google Scholar) and pathways J. Zhukova E. N. Rozengurt E. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, I. S. T. M. A. A. Link G. S. P. Pfizenmaier K. F.J. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Waldron R.T. A. A. Rozengurt E. J. Mol. Cell. 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Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar), and F. G. M. M. Res. 2004; PubMed Scopus Google Scholar). is that the of the PKD are in the regulation of cell and A of has been in the regulatory mechanisms of PKD activation and regulation and the role of novel PKCs in PKD activation As in other activation phosphorylation a mechanism of signal and an role of the in a variety of fundamental biological and the for is well In conclusion, studies of PKD a of both its signal and and its for regulatory with multiple downstream pathways.