The leucine‐rich repeat signaling scaffolds Shoc2 and Erbin: cellular mechanism and role in disease

Abstract

Leucine‐rich repeat‐containing proteins (LRR proteins) are involved in supporting a large number of cellular functions. In this review, we summarize recent advancements in understanding functions of the LRR proteins as signaling scaffolds. In particular, we explore what we have learned about the mechanisms of action of the LRR scaffolds Shoc2 and Erbin and their roles in normal development and disease. We discuss Shoc2 and Erbin in the context of their multiple known interacting partners in various cellular processes and summarize often unexpected functions of these proteins through analysis of their roles in human pathologies. We also review these LRR scaffold proteins as promising therapeutic targets and biomarkers with potential application across various pathologies.

Polycistronic baculovirus expression of SUGT1 enables high-yield production of recombinant leucine-rich repeat proteins and protein complexes

“…MRAS is a member of the RAS family of proteins and shares regulatory and effector proteins (5). SHOC2 is an evolutionarily well-conserved scaffolding protein comprised primarily of leucine rich repeats (LRRs) (6). Scaffold proteins are important regulators in many signaling pathways and act by binding key proteins into complexes, localizing pathway proteins together, and controlling positive and negative feedback.…”

“…Scaffold proteins are important regulators in many signaling pathways and act by binding key proteins into complexes, localizing pathway proteins together, and controlling positive and negative feedback. SHOC2 contributes to modulation of RAF signaling activity through interaction with multiple proteins including RAS, PPP1CA, SCRIB, ERBIN, and HUWE1 (6). SCRIB and ERBIN are LAP (LRR and PDZ domain) proteins which mediate SMP activity by interacting with PPP1CA and SHOC2 to disrupt SMP/RAF1 signaling while HUWE1 is involved in ubiquitination of SHOC2 and RAF1 (6,7).…”

“…SHOC2 contributes to modulation of RAF signaling activity through interaction with multiple proteins including RAS, PPP1CA, SCRIB, ERBIN, and HUWE1 (6). SCRIB and ERBIN are LAP (LRR and PDZ domain) proteins which mediate SMP activity by interacting with PPP1CA and SHOC2 to disrupt SMP/RAF1 signaling while HUWE1 is involved in ubiquitination of SHOC2 and RAF1 (6,7). The final protein in the complex, PPP1CA, is one of a limited number of serine/threonine phosphatases which can form hundreds of distinct protein-protein complexes to specifically dephosphorylate proteins (8,9).…”

Accessory proteins of the RAS-MAPK pathway: moving from the side line to the front line

“…SHOC2 is an integral element of a heterotrimeric holoenzyme complex with PP1 and MRAS, which dephosphorylates and releases RAF from its inhibited state 56,57 , and subsequently activates the MAPK pathway 58 . The scaffold protein Erbin interferes with this process 59 . It binds and sequesters SHOC2 from its RAS/RAF complex, and inhibits ERK activation 60 .…”

“…Legius syndrome-associated mutations in SPRED1, mostly result in loss-of-function of the scaffold protein, and gain-of-function of the RAS-MAPK pathway 105,106 . In contrast, mutations in genes encoding SHP2 and SHOC2 lead to a gain-of-function and contribute to MAPK signalling upregulation that causes diverse developmental phenotypes 56,59,107 . A recurrent activating mutation at the very N-terminus of SHOC2 (Ser-2 to Gly) leads to N-myristoylation of SHOC2, confers continuous membrane association and consequently causes Mazzanti syndrome, a RASopathy characterised by features resembling Noonan syndrome 107,108 .…”