SUR-8, a Conserved Ras-Binding Protein with Leucine-Rich Repeats, Positively Regulates Ras-Mediated Signaling in C. elegans

Abstract

We describe the identification and characterization of a novel gene, sur-8, that positively regulates Ras-mediated signal transduction during C. elegans vulval development. Reduction of sur-8 function suppresses an activated ras mutation and dramatically enhances phenotypes of mpk-1 MAP kinase and ksr-1 mutations, while increase of sur-8 dosage enhances an activated ras mutation. sur-8 appears to act downstream of or in parallel to ras but upstream of raf. sur-8 encodes a conserved protein that is composed predominantly of leucine-rich repeats. The SUR-8 protein interacts directly with Ras but not with the Ras(P34G) mutant protein, suggesting that SUR-8 may mediate its effects through Ras binding. A structural and functional SUR-8 homolog in humans specifically binds K-Ras and N-Ras but not H-Ras in vitro.

Sur8/Shoc2 Involves Both Inhibition of Differentiation and Maintenance of Self-Renewal of Neural Progenitor Cells via Modulation of Extracellular Signal-Regulated Kinase Signaling

“…NPCs retain stem cell characteristics, including a high proliferative potential and the ability to selfrenew [30]. In this study, we identified Sur8, the scaffold protein of the Ras-ERK pathway [6][7][8], as a factor that maintains self-renewal capacity and the undifferentiated state in NPCs. We indicate that Sur8 is an intracellular biomarker for Nestinpositive undifferentiated NPCs.…”

“…The Scaffold proteins such as Sur8, KSR, and MP1 assemble intracellular signaling complexes and can play important roles in cellular responses [3,[46][47][48]. The scaffold proteins can regulate the efficiency of the signaling response by virtue of their ability to form different complexes with the signaling members of the Ras-ERK pathway such as Ras, Raf [7,49], Erbin, and PP1 [6,49]. Concentration of the scaffold proteins influences differential formation of the complexes, resulted in the output of different physiologies [50].…”

“…Sur8 forms a complex with Ras and Raf-1 [8] and positively regulates Ras-and growth factor-mediated ERK pathway activation [6][7][8]. To determine whether the Ras-ERK pathway plays a role in the Sur8-mediated regulation of proliferation and differentiation in NPCs, we measured the effects of Sur8 knockdown or overexpression on ERK activation.…”

“…Sur8 is highly conserved in various eukaryotic organisms, and the Sur8 mutant of C. elegans is complemented by the human homolog of Sur8 [4]. Sur8 is involved in growth factor-mediated activation of the Ras-ERK pathway, acting as a scaffold for Ras and Raf [6][7][8]. Although these studies show that Sur8 is an activator of the Ras-ERK pathway, the physiological role(s) and regulatory mechanisms of Sur8 are poorly understood.…”

La signalisation RTK/RAS/ERK élargie

“…Pour ce qui est des deux homologues de HYP chez les mammifères, SAMD10 (SAM domain containing 10) et SAMD12, aucune étude n'est actuellement disponible à leur sujet. Avec KSR et CNK, une autre protéine d'échafaudage, SUR-8, a été détectée chez C. elegans [33,34]. L'homologue humain de SUR-8 aurait la capacité d'associer RAS et RAF [35].…”