The Two Faces of SHOC2: Skin Homeostasis Regulator and RAS-MAPK Pathway Enhancer.

Abstract

The signaling pathway composed of RAS-RAF-MEK-ERK proteins regulates essential cellular processes such as cell differentiation, proliferation and migration. This pathway is crucial for embryonic development and tissue homeostasis and it is frequently dysregulated in cancer. The scaffold protein SHOC2 is a key modulator of ERK1/2 signals whose activity depends on its subcellular localization. Recently, SHOC2 has been proposed as a therapeutic target for the treatment of several cancers, either alone or in combination with MEK inhibitors. In this review we focus on the role of SHOC2 in the epithelial skin biology and its interaction with other partners to better understand the potential consequences of SHOC2 inhibition, particularly regarding skin toxicities. SHOC2 interacts with RAPTOR to limit mTORC1 activation, thereby promoting autophagy and limiting cell growth. Through its association with MRAS and PP1C, SHOC2 controls RAF1 dephosphorylation and modulates ERK output. Loss of SHOC2 disrupts E-cadherin turnover, impairing junctional dynamics and epithelial migration. In vivo, SHOC2 is essential for tissue development as complete knockout in mice results in embryonic lethality. We also discuss other important SHOC2 interactions in the epidermis including SCRIBBLE and ERBIN. SHOC2 acts as a signaling hub connecting RAS-MAPK pathways with epithelial polarity and differentiation. Its spatial regulation ensures proper tissue homeostasis, whereas mutation or mis-localization drives cancer and developmental disorders such as Noonan- like syndrome with loose anagen hair (NSLH) which has ectodermal manifestations. Finally, we review the context-dependent role of SHOC2 in cancer where it can be either upregulated or downregulated. Reduced SHOC2 activity in tumors addicted to ERK signaling may activate compensatory pathways highlighting the essential importance of SHOC2 in skin homeostasis and the potential cutaneous toxicities of SHOC2- targeted therapies.