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

SHOC2 is a leucine-rich repeat protein that functions as a scaffold critical for RTK/ RAS signaling. RAS proteins are a family of small GTPases that function as binary switches and are critical in development, multiple physiological processes, and diseases (1). The canonical RAS family members HRAS, KRAS, and NRAS have been shown to bind SHOC2 as well as a closely related RRAS subfamily member, MRAS, for muscle RAS homolog. RTKs are upstream regulators of RAS and drive RAS activation in response to growth factor binding (1, 2). Downstream effectors of RAS, including RAF and phosphatidylinositol 3-kinase (PI3K), bind GTP-loaded RAS and function as key mediators of RAS signaling. Upon activation, RAF kinases trigger a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) 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.

Automated summary

SHOC2 is a key scaffold protein that plays a critical role in RTK/RAS signaling, facilitating downstream receptor tyrosine kinase (RTK) and RAS signaling while mediating various cellular and developmental processes.