PKR is a novel functional direct player that coordinates skeletal muscle differentiation via p38MAPK/AKT pathways

Protein Kinase PKR-Dependent Activation of Mitogen-Activated Protein Kinases Occurs through Mitochondrial Adapter IPS-1 and Is Antagonized by Vaccinia Virus E3L

“…Our results obtained with human cells may be related to those of previously reported studies with PKR null mouse cells that yielded seemingly inconsistent and apparently contradictory observations on the role of PKR in MAPK activation (2,11,12,35,37). Our findings for human cells with the stable knockdown of PKR are consistent with some results obtained with PKR null MEF cells (11,12,37); for example, in both human and mouse cells, PKR enhances p38 MAPK activation in response to dsRNA.…”

“…A third possibility is that PKR interacts directly with p38 or JNK MAPKs. Alisi et al and Spaziani et al reported that PKR physically interacts with the p38 protein and that this interaction requires both the N-and C-terminal regions of PKR (2,36). Among these three PKR-protein interaction models, we favor that of the interaction between PKR and TRAF as the most likely mechanism by which PKR regulates the p38 and JNK MAPK activation by dsRNA, based on our observations and those of others that PKR is required for the activation of multiple downstream transcription factors, including IRF-3, NF-B, and ATF-2/c-Jun, in the RLR signaling pathway induced by dsRNA (1,4,16,23,53).…”

“…The PKR protein has been proposed previously to be directly involved in the p38 and JNK kinase signaling, based on the results of studies using cells derived from Pkr genetic knockout mice, including mouse embryonic fibroblasts (MEFs) and bone marrow macrophages, that have shown that PKR and the stress-activated MAPKs both contribute to stress-activated responses (2,11,13,35,37). But the role of PKR in the activation process of p38 MAPK implied from the findings of these studies remains controversial.…”

“…But the role of PKR in the activation process of p38 MAPK implied from the findings of these studies remains controversial. For example, the PKRdependent activation of p38 MAPK in mouse cells is described as occurring in response to bacterial endotoxin (13) and during skeletal muscle cell differentiation (2), but studies with Pkr null mouse cells have yielded conflicting results for a possible role of PKR in dsRNA-dependent signaling to activate p38 MAPK (13). Furthermore, while two groups found that PKR is required for p38 MAPK activation by LPS, poly(I:C), or TNF-␣ in both primary and immortalized MEFs and that PKR is also required for JNK activation but only in primary MEFs (2,11,13), another group reported an apparently contradictory finding that the depletion of PKR in the Pkr Ϫ/Ϫ MEF cells potentiates p38 MAPK activation but inhibits JNK activation in response to TNF-␣ (37).…”

Autophagy Induction by Capsaicin in Malignant Human Breast Cells Is Modulated by p38 and Extracellular Signal-Regulated Mitogen-Activated Protein Kinases and Retards Cell Death by Suppressing Endoplasmic Reticulum Stress-Mediated Apoptosis

“…Furthermore, the p38-Akt signaling pathway has been reported to play an important role in muscle differentiation (Cabane et al, 2004;Alisi et al, 2008). Collectively, these studies suggest that p38-Akt signaling is associated with cell survival.…”