Feedback regulation of MAPK signalling by an RNA-binding protein

Abstract

Mitogen-activated protein kinases (MAPKs) are evolutionarily conserved enzymes that convert extracellular signals into various outputs such as cell growth, differentiation and cell death. MAPK phosphatases selectively inactivate MAPKs by dephosphorylating critical phosphothreonine and phosphotyrosine residues. The transcriptional induction of MAPK phosphatase expression by various stimuli, including MAPK activation, has been well documented as a negative-feedback mechanism of MAPK signalling. Here we show that Rnc1, a novel K-homology-type RNA-binding protein in fission yeast, binds and stabilizes Pmp1 messenger RNA, the MAPK phosphatase for Pmk1 (refs 10, 11). Rnc1 therefore acts as a negative regulator of Pmk1 signalling. Notably, Pmk1 phosphorylates Rnc1, causing enhancement of the RNA-binding activity of Rnc1. Thus, Rnc1 is a component of a new negative-feedback loop that regulates the Pmk1 pathway through its binding to Pmp1 mRNA. Our findings--the post-transcriptional mRNA stabilization of a MAPK phosphatase mediated by an RNA-binding protein--provide an additional regulatory mechanism for fine-tuning of MAPK signalling pathways.

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…Whereas MEK1/2 activates ERK1/2, MKK3/6 is responsible for p38 phosphorylation, MKK4/7 regulates JNK MAPKs and MEK5 is responsible for ERK5 activation (reviewed by Chang and Karin, 2001). This network is further complicated by several regulatory feedback mechanisms (Sugiura et al, 2003;Sweeney and Carraway, 2004).…”

Role of the RNA-binding Protein Nrd1 and Pmk1 Mitogen-activated Protein Kinase in the Regulation of Myosin mRNA Stability in Fission Yeast

“…To test this possibility, we examined the effects of a series of MAPK-deletion strains on the temperature-sensitive phenotype of the cdc4-8 mutants. Notably, the deletion of Pmk1 MAPK, which regulates cell integrity (Toda et al, 1996;Sugiura et al, 1999Sugiura et al, , 2003, suppressed the temperature sensitivity of the cdc4-8 mutant cells ( Figure 6A, cdc4-8⌬pmk1). In contrast, the deletion of Spk1 MAPK, which regulates meiosis (Gotoh et al, 1993;Figure 6A, cdc4-8⌬spk1), or the deletion of Spc1/Sty1 MAPK, a homologue of p38 in fission yeast (Millar et al, 1995;Degols et al, 1996), did not suppress the temperature-sensitive growth of cdc4-8 mutant cells ( Figure 6A, cdc4-8⌬spc1).…”

“…The Pmk1 MAPK pathway plays a key role in cytokinesis, cell wall integrity, and ion homeostasis (Toda et al, 1996;Sugiura et al, 1999Sugiura et al, , 2003; however, no physiological Pmk1 substrate involved in cytokinesis has been identified. Nrd1, by serving as a MAPK target and as an RNA-binding factor of an essential myosin light chain, responds to extracellular signals mediated by MAPK signaling and fine tunes myosin expression by switching off its RNA-binding property.…”

“…The mRNA stability was determined as described in Sugiura et al (2003). The fractions of mRNA remaining were normalized to the level of Leu1 mRNA to control for loading error.…”

“…Notably, Pmk1, the mitogen-activated protein kinase (MAPK), which regulates cell integrity (Toda et al, 1996;Sugiura et al, 1999;Sugiura et al, 2003), directly phosphorylates Nrd1, thereby negatively regulating the activity of Nrd1 to bind to and stabilize Cdc4 mRNA. We propose that the MAPK-dependent phosphorylation of the RNA-binding protein Nrd1 may serve as a novel mechanism for the regulation of myosin mRNA and cytokinesis in fission yeast.…”