SHOC2

SHOC2
Identifiers
Aliases	SHOC2 , SIAA0862, SOC2, SUR8, SHOC2 leucine-rich repeat scaffold protein, leucine rich repeat scaffold protein, SHOC2 leucine rich repeat scaffold protein, NSLH1
External IDs	OMIM: 602775; MGI: 1927197; HomoloGene: 7219; GeneCards: SHOC2; OMA:SHOC2 - orthologs
Gene location (Human) Chr. Chromosome 10 (human) [1] Band 10q25.2 Start 110,919,367 bp [1] End 111,017,307 bp [1]
Gene location (Mouse) Chr. Chromosome 19 (mouse) [2] Band 19|19 D2 Start 53,932,737 bp [2] End 54,021,564 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Achilles tendon sural nerve bone marrow epithelium of colon bone marrow cells tail of epididymis testicle corpus epididymis jejunal mucosa caput epididymis Top expressed in genital tubercle ascending aorta aortic valve pineal gland tail of embryo superior cervical ganglion dorsomedial hypothalamic nucleus pyloric antrum renal corpuscle hair follicle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein phosphatase 1 binding protein phosphatase regulator activity protein phosphatase binding protein binding protein serine/threonine phosphatase activity Cellular component protein phosphatase type 1 complex nucleoplasm nucleus cytoplasm cytosol plasma membrane photoreceptor inner segment photoreceptor outer segment membrane Biological process fibroblast growth factor receptor signaling pathway positive regulation of Ras protein signal transduction Ras protein signal transduction regulation of phosphoprotein phosphatase activity protein dephosphorylation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 8036 56392 Ensembl ENSG00000108061 ENSMUSG00000024976 UniProt Q9UQ13 O88520 RefSeq (mRNA) NM_001269039 NM_007373 NM_001324336 NM_001324337 NM_001168505 NM_019658 NM_001355242 RefSeq (protein) NP_001255968 NP_001311265 NP_001311266 NP_031399 NP_001161977 NP_062632 NP_001342171 Location (UCSC) Chr 10: 110.92 – 111.02 Mb Chr 19: 53.93 – 54.02 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.

Leucine-rich repeat (LRR) protein SHOC-2 is a protein that in humans is encoded by the SHOC2 gene. ^{[5] [6] [7] [8]} 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. ^[9] 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. ^[10]

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. ^[9] 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. GRCh38: Ensembl release 89: ENSG00000108061 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024976 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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.
6. 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.
7. 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.
8. "Entrez Gene: SHOC2 soc-2 suppressor of clear homolog (C. elegans)".
9. 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.
10. 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

• Dai P, Xiong WC, Mei L (2006). "Erbin inhibits RAF activation by disrupting the sur-8-Ras-Raf complex". J. Biol. Chem. 281 (2): 927–33. doi: 10.1074/jbc.M507360200 . PMID   16301319.
• Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (1998). "Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Res. 5 (6): 355–64. doi: 10.1093/dnares/5.6.355 . PMID   10048485.