A Leucine-Rich Repeat Protein Provides a SHOC2 the RAS Circuit: a Structure-Function Perspective

Mol Cell Biol. 2021 Mar 24;41(4):e00627-20. doi: 10.1128/MCB.00627-20. Print 2021 Mar 24.

Abstract

SHOC2 is a prototypical leucine-rich repeat protein that promotes downstream receptor tyrosine kinase (RTK)/RAS signaling and plays important roles in several cellular and developmental processes. Gain-of-function germ line mutations of SHOC2 drive the RASopathy Noonan-like syndrome, and SHOC2 mediates adaptive resistance to mitogen-activated protein kinase (MAPK) inhibitors. Similar to many scaffolding proteins, SHOC2 facilitates signal transduction by enabling proximal protein interactions and regulating the subcellular localization of its binding partners. Here, we review the structural features of SHOC2 that mediate its known functions, discuss these elements in the context of various binding partners and signaling pathways, and highlight areas of SHOC2 biology where a consensus view has not yet emerged.

Keywords: MAPK signaling; Noonan syndrome; PP1C; RAF; RAS; SHOC2; cancer; leucine-rich repeat; receptor tyrosine kinase.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Leucine-Rich Repeat Proteins
  • MAP Kinase Signaling System
  • Proteins / metabolism*
  • Signal Transduction / physiology
  • ras Proteins / metabolism*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Leucine-Rich Repeat Proteins
  • Proteins
  • SHOC2 protein, human
  • ras Proteins