SHOC2

Leucine-rich repeat (LRR) protein SHOC-2 is a protein that in humans is encoded by the SHOC2 gene.[1][2][3][4] The best-studied role of SHOC2 is in modulating signals of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway by forming a holophosphatase complex that activates RAF proteins(PMID 16630891, 33526449). This protein was initially identified in Caenorhabditis elegans as SUR-8/SOC2 and was found to be a critical positive regulator of the ERK1/2 signaling pathway that integrates the Ras and RAF components of the ERK1/2 pathway into a multiprotein complex.[5] Specifically, SHOC2 tethers RAS and PP1C proteins and in close proximity to RAF to dephosphorylate “S259” to enable MAPK signaling. It has been shown that activity that results in lipidation (specifically Myristoylation) of SHOC2 can cause Noonan syndrome.[6]

Biological assembly of SHOC2 protein as shown by crystal structure to a resolution of 2.4 Angstrom. Sulfate molecules are labeled purple. Structure from 10.2210/pdb7TVG/pdb.
SHOC2 protein leucine rich domain. Leucine amino acids shown as bright orange sticks.

Interactions

SHOC2 has been shown to interact with the catalytic phosphatase subunit PP1C(PMID 16630891) and MRAS as well as canonical RAS isoforms (H/K/NRAS)(PMID 35768504, 35831509, 35830882). The ternary complex SHOC2-RAS-PP1C functions to dephosphorylate an inhibitory phosphorylation site ('S259') on RAF family proteins to enable MAPK signaling(PMID 16630891).

SHOC2 Dependent Dynamic Regulation of MAPK signaling

The amplitude of SHOC2-mediated ERK1/2 signals has been proposed to be regulated by differential regulation of RAF activation at the plasma membrane and internalized endosome compartment (PMID 31213532) as well an alternative model proposing post-translational modifications(PMID 25022756). SHOC2 ubiquitination mediated by HUWE1 is triggered by growth factor activation of the ERK1/2 pathway and is a prerequisite for the subsequent ubiquitination of the RAF-1 kinase associated with SHOC2.[5] However, the current data has yet to address how these ubiquitin modifications regulate the SHOC2 holophosphatase function to reduce the amplitude of RAF-ERK1/2 signals.

References
  1. Selfors LM, Schutzman JL, Borland CZ, Stern MJ (Jul 1998). "soc-2 encodes a leucine-rich repeat protein implicated in fibroblast growth factor receptor signaling". Proc. Natl. Acad. Sci. U.S.A. 95 (12): 6903–8. Bibcode:1998PNAS...95.6903S. doi:10.1073/pnas.95.12.6903. PMC 22679. PMID 9618511.
  2. Sieburth DS, Sun Q, Han M (Aug 1998). "SUR-8, a conserved Ras-binding protein with leucine-rich repeats, positively regulates Ras-mediated signaling in C. elegans". Cell. 94 (1): 119–30. doi:10.1016/S0092-8674(00)81227-1. PMID 9674433. S2CID 13102676.
  3. Li W, Han M, Guan KL (May 2000). "The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf". Genes Dev. 14 (8): 895–900. doi:10.1101/gad.14.8.895. PMC 316541. PMID 10783161.
  4. "Entrez Gene: SHOC2 soc-2 suppressor of clear homolog (C. elegans)".
  5. Jang, Eun Ryoung; Shi, Ping; Bryant, Jamal; Chen, Jing; Dukhande, Vikas; Gentry, Matthew S.; Jang, HyeIn; Jeoung, Myoungkun; Galperin, Emilia (October 2014). "HUWE1 Is a Molecular Link Controlling RAF-1 Activity Supported by the Shoc2 Scaffold". Molecular and Cellular Biology. 34 (19): 3579–3593. doi:10.1128/MCB.00811-14. ISSN 0270-7306. PMC 4187736. PMID 25022756.
  6. Cordeddu V, Di Schiavi E, Pennacchio LA, Ma'ayan A, Sarkozy A, Fodale V, Cecchetti S, Cardinale A, Martin J, Schackwitz W, Lipzen A, Zampino G, Mazzanti L, Digilio MC, Martinelli S, Flex E, Lepri F, Bartholdi D, Kutsche K, Ferrero GB, Anichini C, Selicorni A, Rossi C, Tenconi R, Zenker M, Merlo D, Dallapiccola B, Iyengar R, Bazzicalupo P, Gelb BD, Tartaglia M (Sep 2009). "Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair". Nature Genetics. 41 (9): 1022–6. doi:10.1038/ng.425. PMC 2765465. PMID 19684605.

Further reading


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