Regulation of Smad signaling by protein kinase C

Abstract

Cross talk between transforming growth factor b(TGF-b) serine/threonine kinase receptor signaling and tyrosine kinase receptor signaling modulates cell responsiveness to polypeptide growth factors regulating cell proliferation, differentiation, and apoptosis. Here we provide a mechanism through which Smad-dependent TGF-b signaling is modulated by protein kinase C (PKC). PKC, for example, is activated downstream of tyrosine kinase receptors. We show that PKC directly phosphorylates receptor-regulated Smad proteins. This phosphorylation abrogates the ability of Smad3 to bind directly to DNA, which leads to subsequent inability to mediate transcriptional responses dependent on the direct binding of Smad3 to DNA. Interference with PKC regulation of Smad functions increased cell sensitivity to transformation by the tumor promoter phorbol 12-myristate 13-acetate (PMA). PKC-dependent phosphorylation of Smad3 was found also to be a key event in the PMA-dependent inactivation of TGF-b-stimulated cell death. Thus, PKC-dependent phosphorylation of Smad3 leads to down-regulation of the growth inhibitory and apoptotic action of TGF-b.

Glioblastoma-secreted factors induce IGFBP7 and angiogenesis by modulating Smad-2-dependent TGF-β signaling

“…However, as SB431542 partially blocked these responses, the phosphorylation of Smad-1/-5 appears to be in part secondary to the activation of ALK5. TGF-b1 can also act through receptor-dependent, but Smadindependent pathways, including the activation of mitogen-activated protein kinase (Blanchette et al, 2001), c-Jun N-terminal kinase (Engel et al, 1999) and protein kinase C (Yakymovych et al, 2001).…”

Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase Cα

“…MEKK1 or JNK enhanced Smad phosphorylation, nuclear localization, and Smad-mediated transcription (44,45). In contrast, the phosphorylation of R-Smads at the linker domain or MH-1 domain induced by Ras/Erk/MAPK, CDK2/4, and PKC inhibited the activation of Smad signaling (23,43,46,47). Yakymovych et al (23) reported that PKC activation resulted in the phosphorylation of the MH1 domains of Smad2 and Smad3 to abrogate DNA binding of Smad3.…”

“…Interestingly, several studies have reported that PKC interacts with the TGF-h/BMP signaling pathway (23)(24)(25). PKC-dependent phosphorylation of the MH1 domain of TGF-h-specific Smads (Smad2/3) led to down-regulation of the growth-inhibitory and apoptotic action of TGF-h (23).…”

“…PKC-dependent phosphorylation of the MH1 domain of TGF-h-specific Smads (Smad2/3) led to down-regulation of the growth-inhibitory and apoptotic action of TGF-h (23). In contrast, BMP-2 enhances apoptosis by using the PKC-dependent signaling pathway in human osteoblasts (24).…”

To (TGF)β or not to (TGF)β: Fine-tuning of Smad signaling via post-translational modifications

“…Additional kinases, e.g. MEKK-1, CaMKII, protein kinase C, and CKε, target R-Smads and regulate Smad-dependent transcriptional responses [36][37][38][39], and TGF-β may also induce Smad phosphorylation in the linker region as well as at the SXS motif [31,32]. Thus, the Smad linker region is emerging as an important and critical regulatory platform in the fine-tuning of TGF-β signaling.…”