Protein Kinase D Is Sufficient to Suppress EGF-Induced c-Jun Ser 63 Phosphorylation

Hurd, Cliff

doi:10.1006/bbrc.2001.4591

Cited by 37 publications

(39 citation statements)

References 23 publications

(19 reference statements)

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“…In agreement with this, inducible overexpression of kinaseactive PKD-S744E/S748E reduced c-jun Ser63 phosphorylation in response to EGF stimulation in HEK 293 cells [9]. More recent reports advance the concept that PKD activity modulates JNK signaling to c-jun at multiple levels.…”

supporting

confidence: 58%

Identification of a novel phosphorylation site in c-jun directly targeted in vitro by protein kinase D

Waldron

Whitelegge

Faull

2007

Biochemical and Biophysical Research Communications

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Protein kinase D (PKD) phosphorylates the c-jun amino-terminal in vitro at site(s) distinct from JNK [C. Hurd, R.T. Waldron, E. Rozengurt, Protein kinase D complexes with c-jun N-terminal kinase via activation loop phosphorylation and phosphorylates the c-jun N-terminus, Oncogene 21 (2002) 2154-2160], but the sites have not been identified. Here, metabolic 32 P-labeling of c-jun protein in COS-7 cells indicated that PKD phosphorylates c-jun in vivo at a site(s) between aa 43-93, a region containing important functional elements. On this basis, the PKD-mediated phosphorylation site(s) was further characterized in vitro using GST-c-jun fusion proteins. PKD did not incorporate phosphate into Ser63 and Ser73, the JNK sites in GST-c-jun(1-89). Rather, PKD and JNK could sequentially phosphorylate distinct site(s) simultaneously. By mass spectrometry of tryptic phosphopeptides, Ser58 interposed between the JNK-binding portion of the delta domain and the adjacent TAD1 was identified as a prominent site phosphorylated in vitro by PKD. These data were further supported by kinase reactions using truncations or point-mutations of GST-c-jun. Together, these data suggest that PKD-mediated phosphorylation modulates c-jun at the level of its N-terminal functional domains.

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supporting

confidence: 58%

Identification of a novel phosphorylation site in c-jun directly targeted in vitro by protein kinase D

Waldron

Whitelegge

Faull

2007

Biochemical and Biophysical Research Communications

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“…Interestingly, three independent laboratories, including our own, have demonstrated attenuation of pro-apoptotic JNK signaling by PKD (49, 90 -92). For example, induced expression of an activated mutant of PKD was sufficient to suppress EGF-stimulated c-Jun phosphorylation at Ser-63, a natural substrate of JNK (91). In view of the opposite effects exerted by PKD on the activity and duration of the ERK and JNK pathways, PKD emerges as a critical element in regulating such fundamental cellular functions as cell fate and proliferation.…”

Section: Increased Duration Of Erk Signaling Mediates the Potentiatiomentioning

confidence: 99%

Protein Kinase D Potentiates DNA Synthesis Induced by Gq-coupled Receptors by Increasing the Duration of ERK Signaling in Swiss 3T3 Cells

Sinnett‐Smith

Zhukova

Hsieh

et al. 2004

Journal of Biological Chemistry

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108

115

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Neuropeptides are implicated as growth factors in a variety of fundamental processes including development, inflammation, tissue regeneration, and neoplastic transformation (1-3). In particular, bombesin and its mammalian counterpart gastrin-releasing peptide bind to a GPCR 1 (4, 5) that promotes G␣ q -mediated activation of ␤ isoforms of phospholipase C (6 -8) to produce 2 s messengers: Ins(1,4,5)P 3 that mobilizes Ca 2ϩ from internal stores and diacylglycerol that activates conventional (␣, ␤ 1 , ␤ 2 , and ␥) and novel (␦, ⑀, , and ) PKCs (9, 10). The bombesin/gastrin-releasing peptide GPCR also interacts with members of the G 12 family leading to Rho-dependent actin remodeling and tyrosine phosphorylation of focal adhesion proteins, including FAK (10 -17). Subsequently, bombesin induces striking activation of serine phosphorylation cascades (11)(12)(13)(14) and promotes increased expression of immediate early response genes, stimulation of DNA synthesis, and cell proliferation (15-19). The mechanism(s) linking the early signaling pathways to the subsequent stimulation of cell proliferation remains incompletely understood.PKD (also initially known as PKC) is a serine/threonine protein kinase with structural, enzymology, and regulatory properties different from the PKC family members (20, 21). PKD most distinct characteristics are the presence of a catalytic domain distantly related to Ca 2ϩ -regulated kinases, a pleckstrin homology (PH) region that regulates enzyme activity and a highly hydrophobic stretch of amino acids in its Nterminal region (22)(23)(24). This N-terminal region also contains a tandem repeat of cysteine-rich, zinc finger-like motifs, which confers high affinity for phorbol esters and plays a negative role in the regulation of catalytic kinase activity (25-28). The identification of PKD-2 and PKD-3, similar in overall structure, primary amino acid sequence, and enzymology properties to PKD/PKC (29 -32), supports the notion that PKD isoenzymes constitute a separate family of serine protein kinases.PKD can be activated in intact cells through multiple G protein pathways, including G q , G i , and G 12 (33-39), as well as by biologically active phorbol esters, growth factors and antigen-receptor engagement (36, 37, 39 -45). In all these cases, rapid PKD activation is mediated by PKC-dependent phosphorylation of Ser-744 and Ser-748 within the activation loop of the catalytic domain of PKD (33, 46 -48). PKD activation is associated with its translocation to the plasma membrane and subsequent transient accumulation in the nucleus (25,28,50,51). These findings revealed that PKD is activated by multiple growth-promoting factors (22, 52) suggesting that it functions in mitogenic signaling. Indeed, we reported that PKD overexpression markedly potentiates DNA synthesis induced by the GPCR agonists bombesin and vasopressin in Swiss 3T3 cells (53), a cell line that has been used extensively as a model system to elucidate signal transduction pathways in the mitogenic action of GPCR agonists (1,54,55). Thes...

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“…Several laboratories have shown that PKC/PKD activation negatively interferes with the activation of the JNK pathway (13,28,29). JNK has been shown to colocalize with PKD upon overexpression in COS cells (30).…”

Section: Right-hand Panels)mentioning

confidence: 99%

Protein Kinase Cμ Regulation of the JNK Pathway Is Triggered via Phosphoinositide-dependent Kinase 1 and Protein Kinase Cε

Brändlin

Eiseler

Salowsky

et al. 2002

Journal of Biological Chemistry

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Protein Kinase D Is Sufficient to Suppress EGF-Induced c-Jun Ser 63 Phosphorylation

Cited by 37 publications

References 23 publications

Identification of a novel phosphorylation site in c-jun directly targeted in vitro by protein kinase D

Identification of a novel phosphorylation site in c-jun directly targeted in vitro by protein kinase D

Protein Kinase D Potentiates DNA Synthesis Induced by Gq-coupled Receptors by Increasing the Duration of ERK Signaling in Swiss 3T3 Cells

Protein Kinase Cμ Regulation of the JNK Pathway Is Triggered via Phosphoinositide-dependent Kinase 1 and Protein Kinase Cε

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