Protein Kinase C (PKC)η-mediated PKCμ Activation Modulates ERK and JNK Signal Pathways

Abstract

Protein kinase C (PKC), a family of lipid-activated serine kinases, is involved in multiple functions in the regulation of growth control. The PKC-related isoform PKC/PKD has been implicated in mitogenic signal cascades because of the activation of p42/p44 MAPK leading to Elk1-mediated gene transcription, and PKC/PKD has been shown to be activated via a PKC-dependent pathway. By using confocal analyses, we demonstrate here that PKC partially colocalizes with PKC in different cell types. Colocalization depends on the presence of the PKC pleckstrin homology domain. Coexpression of constitutively active PKC with PKC leads to a significant enhancement of the PKC substrate phosphorylation capacity as a result of an increased phosphorylation of the activation loop Ser 738/742 of PKC, whereas Ser 910 autophosphorylation remains unaffected. In vitro phosphorylation experiments show that PKC directly phosphorylates PKC on activation loop serines. Consequently, the p42 MAPK cascade is triggered leading to an increase in reporter gene activity driven by a serum-responsive element in HEK293 cells. At the same time, PKC-mediated JNK activation is reduced, providing evidence for a mutual regulation of PKC/PKC affecting different arms of the p38/ERK/ JNK pathways. Our data provide evidence for the sequential involvement of selective PKC isoforms in kinase cascades and identify the relevant domains in PKC for interaction with and activation by PKC as pleckstrin homology domain and activation loop.

The Role of Protein Kinase D in Neurotensin Secretion Mediated by Protein Kinase C-α/-δ and Rho/Rho Kinase

“…For example, activation of PKD can occur through activation of PKC-⑀ in HEK393 cells (22), PKC-in COS-7 cells (26), and PKC-in T cells (25). We demonstrate PKD phosphorylation was inhibited in the novel human endocrine cell line BON by pretreatment with PKC inhibitors and by PKC-␣ and -␦ siRNA and enhanced by overexpression of wild-type PKC-␣ and -␦.…”

“…PMA-mediated PKD Activation-PKD is activated in a PKCdependent fashion in some cell types (23)(24)(25)(26). To determine whether PKC isoforms are involved in PMA-induced PKD activation in BON cells, we examined the effect of three PKC inhibitors, Gö6983, GFX, and Ro31-8220, which inhibit activity of classic and novel PKC isoforms but not PKD (49,50) (Fig.…”

“…Expression of PKD has been demonstrated in some endocrine cells, including insulin-and gastrin-secreting cells (20 -22). PKD activation occurs through several mediators via a PKC-dependent pathway (23)(24)(25)(26).…”

“…Expression of PKD has been demonstrated in some endocrine cells, including insulin-and gastrin-secreting cells (20 -22). PKD activation occurs through several mediators via a PKC-dependent pathway (23)(24)(25)(26).Recent studies indicate a close association between PKC isoforms and members of the Rho family of small GTP-binding proteins including Rho (A, B, and C), Rac1, and Cdc42 (27,28). The Rho family members, well-known regulators of the actin cytoskeleton and phosphoinositide metabolism (29), have been implicated in hormone secretion from endocrine cells (30 -32).…”

Protein kinase D: a new player among the signaling proteins that regulate functions in the nervous system

“…For example, G-proteincoupled receptors or receptor tyrosine kinases that activate PLC and PKCε or PKCη cause the phosphorylation of PKD at Ser744 and Ser748 in the activation loop [16][17][18][19] . Second, Gβγ subunits directly activate PKD1 [20][21][22] .…”