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SHOC2

From Wikipedia, the free encyclopedia

SHOC2
Identifiers
AliasesSHOC2, SIAA0862, SOC2, SUR8, SHOC2 leucine-rich repeat scaffold protein, leucine rich repeat scaffold protein, SHOC2 leucine rich repeat scaffold protein, NSLH1
External IDsOMIM: 602775; MGI: 1927197; GeneCards: SHOC2
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
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 MbChr 19: 53.93 – 54.02 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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 protein SHOC-2 is a protein that in humans is encoded by the SHOC2 gene.[5][6][7][8]

Function

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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.

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.[10][11]

Dynamic regulation of MAPK signaling

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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[12] as well an alternative model proposing post-translational modifications.[9] 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.

Clinical significance

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It has been shown that activity that results in lipidation (specifically Myristoylation) of SHOC2 can cause Noonan syndrome.[13]

Interactions

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SHOC2 has been shown to interact with the catalytic phosphatase subunit PP1C[10] and MRAS as well as canonical RAS isoforms (H/K/NRAS).[14][15][16] The ternary complex SHOC2-RAS-PP1C functions to dephosphorylate an inhibitory phosphorylation site ('S259') on RAF family proteins to enable MAPK signaling.[10]

References

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  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000108061 – Ensembl, May 2017
  2. 1 2 3 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 (July 1998). "soc-2 encodes a leucine-rich repeat protein implicated in fibroblast growth factor receptor signaling". Proceedings of the National Academy of Sciences of the United States of America. 95 (12): 6903–6908. Bibcode:1998PNAS...95.6903S. doi:10.1073/pnas.95.12.6903. PMC 22679. PMID 9618511.
  6. ↑ Sieburth DS, Sun Q, Han M (August 1998). "SUR-8, a conserved Ras-binding protein with leucine-rich repeats, positively regulates Ras-mediated signaling in C. elegans". Cell. 94 (1): 119–130. 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 & Development. 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. 1 2 3 Jang ER, Shi P, Bryant J, Chen J, Dukhande V, Gentry MS, et al. (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. PMC 4187736. PMID 25022756.
  10. 1 2 3 Rodriguez-Viciana P, Oses-Prieto J, Burlingame A, Fried M, McCormick F (April 2006). "A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity". Molecular Cell. 22: 217–230. doi:10.1016/j.molcel.2006.03.027. PMID 16630891.
  11. ↑ Kwon JJ, Hahn WC (2021). "A Leucine-Rich Repeat Protein Provides a SHOC2 the RAS Circuit: a Structure-Function Perspective". Molecular and Cellular Biology. 41 e00627-20. doi:10.1128/MCB.00627-20. PMC 8088128. PMID 33526449.
  12. ↑ Boned Del RI, Young LC, Sari S, Jones GG, Ringham-Terry B, Hartig N, et al. (2019). "SHOC2 complex-driven RAF dimerization selectively contributes to ERK pathway dynamics". Proceedings of the National Academy of Sciences of the United States of America. 116: 13330–13339. doi:10.1073/pnas.1902658116. PMC 6613145. PMID 31213532.
  13. ↑ Cordeddu V, Di Schiavi E, Pennacchio LA, Ma'ayan A, Sarkozy A, Fodale V, et al. (September 2009). "Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair". Nature Genetics. 41 (9): 1022–1026. doi:10.1038/ng.425. PMC 2765465. PMID 19684605.
  14. ↑ Liau NP, Johnson MC, Izadi S, Gerosa L, Hammel M, Bruning JM, et al. (2022). "Structural basis for SHOC2 modulation of RAS signalling". Nature. 609: 400–407. doi:10.1038/s41586-022-04838-3. PMC 9452301. PMID 35768504.
  15. ↑ Kwon JJ, Hajian B, Bian Y, Young LC, Amor AJ, Fuller JR, et al. (2022). "Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex". Nature. 609: 408–415. doi:10.1038/s41586-022-04928-2. PMC 9694338. PMID 35831509.
  16. ↑ Hauseman ZJ, Fodor M, Dhembi A, Viscomi J, Egli D, Bleu M, et al. (2022). "Structure of the MRAS-SHOC2-PP1C phosphatase complex". Nature. 609: 416–423. doi:10.1038/s41586-022-05086-1. PMC 9452295. PMID 35830882.

Further reading

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