Protein Arginine Methyltransferase 5 Regulates ERK1/2 Signal Transduction Amplitude and Cell Fate Through CRAF

Abstract

The RAS to extracellular signal-regulated kinase (ERK) signal transduction cascade is crucial to cell proliferation, differentiation, and survival. Although numerous growth factors activate the RAS-ERK pathway, they can have different effects on the amplitude and duration of the ERK signal and, therefore, on the biological consequences. For instance, nerve growth factor, which elicits a larger and more sustained increase in ERK phosphorylation in PC12 cells than does epidermal growth factor (EGF), stimulates PC12 cell differentiation, whereas EGF stimulates PC12 cell proliferation. Here, we show that protein arginine methylation limits the ERK1/2 signal elicited by particular growth factors in different cell types from various species. We found that this restriction in ERK1/2 phosphorylation depended on methylation of RAF proteins by protein arginine methyltransferase 5 (PRMT5). PRMT5-dependent methylation enhanced the degradation of activated CRAF and BRAF, thereby reducing their catalytic activity. Inhibition of PRMT5 activity or expression of RAF mutants that could not be methylated not only affected the amplitude and duration of ERK phosphorylation in response to growth factors but also redirected the response of PC12 cells to EGF from proliferation to differentiation. This additional level of regulation within the RAS pathway may lead to the identification of new targets for therapeutic intervention.

Methylthioadenosine (MTA) Regulates Liver Cells Proteome and Methylproteome: Implications in Liver Biology and Disease

“…Moreover, decreased KRT 8 and 18 promotes the inactivation of ERK1/2 and apoptosis upon activation of the FAS receptor (62). Interestingly, accumulation of MTA in SK-Hep1 cells led to ERK hyperphosphorylation while expression of MTAP and recovery of control MTA concentration induced ERK dephosphorylation, in agreement with previous observations in melanoma cells, suggesting the regulation of the rat sarcoma-rapidly accelerated fibrosarcoma-ERK pathway by MTA (63). The RAF protein has a PRMT5-specific GlyArgGly motif where R563 is dimethylated symmetrically, favoring its degradation (64).…”

“…The RAF protein has a PRMT5-specific GlyArgGly motif where R563 is dimethylated symmetrically, favoring its degradation (64). Accumulation of intracellular MTA inhibits RAF Arg 563 methylation increasing its stability, which might lead to ERK overactivation (48,63).…”

Methylthioadenosine promotes remyelination by inducing oligodendrocyte differentiation

“…activating serine-threonine phosphatase 1 that leads to the dephosphorylation of SR proteins), proliferation, differentiation and apoptosis; or inhibiting protein and DNA methylation by competing with S-adenosylmethionine for methyltransferases [8,9]. Methylthioadenosine is a selective inhibitor of protein arginine methyltransferase 5 (PRMT5) activity [10,11], which in turn dampens cRAF methylation and degradation; this cRAF being responsible for increasing MEK1-2 and STAT3 phosphorylation [12]. Methylthioadenosine also exhibits immunomodulatory activity by suppressing the production of pro-inflammatory cytokines and enhancing the production of antiinflammatory cytokines through an interaction with the nuclear factor kappa B (NFkB) pathway.…”

Retinoic-acid-mediated HRas stabilization induces neuronal differentiation of neural stem cells during brain development

“…We found that the increment or decrement of neuronal differentiation by HRas overexpression or knockdown did not induce proliferation or reduce survival of NSCs, respectively. RTKRas signaling events elicit different biological responses through sustained versus transient activation of downstream effectors (Andreu-Perez et al, 2011). Hence, we measured the activity of HRas, and observed an activation of HRas with its stabilization during differentiation of NSCs.…”