SHOC2

{{Infobox gene}} thumb|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.thumb|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.<ref name="pmid9618511">{{cite journal | vauthors = Selfors LM, Schutzman JL, Borland CZ, Stern MJ | title = soc-2 encodes a leucine-rich repeat protein implicated in fibroblast growth factor receptor signaling | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 12 | pages = 6903–8 | date = Jul 1998 | pmid = 9618511 | pmc = 22679 | doi = 10.1073/pnas.95.12.6903 | bibcode = 1998PNAS...95.6903S | doi-access = free }}</ref><ref name="pmid9674433">{{cite journal | vauthors = Sieburth DS, Sun Q, Han M | title = SUR-8, a conserved Ras-binding protein with leucine-rich repeats, positively regulates Ras-mediated signaling in C. elegans | journal = Cell | volume = 94 | issue = 1 | pages = 119–30 | date = Aug 1998 | pmid = 9674433 | doi = 10.1016/S0092-8674(00)81227-1 | s2cid = 13102676 | doi-access = free }}</ref><ref name="pmid10783161">{{cite journal | vauthors = Li W, Han M, Guan KL | title = The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf | journal = Genes Dev. | volume = 14 | issue = 8 | pages = 895–900 | date = May 2000 | doi = 10.1101/gad.14.8.895 | pmid = 10783161 | pmc = 316541 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SHOC2 soc-2 suppressor of clear homolog (C. elegans)| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=8036}}</ref> 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.<ref>{{cite journal | pmid = 16630891 | doi=10.1016/j.molcel.2006.03.027 | volume=22 | title=A phosphatase holoenzyme {{sic|comprised |hide=y|of}} Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity | date=April 2006 | journal=Mol. Cell | pages=217–30 | vauthors=Rodriguez-Viciana P, Oses-Prieto J, Burlingame A, Fried M, McCormick F}}</ref><ref>{{cite journal | pmid = 33526449 | doi=10.1128/MCB.00627-20 | volume=41 | title=A Leucine-Rich Repeat Protein Provides a SHOC2 the RAS Circuit: a Structure-Function Perspective | pmc=8088128 | year=2021 | journal=Mol Cell Biol | vauthors=Kwon JJ, Hahn WC}}</ref> 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.<ref name=":1">{{Cite journal |last1=Jang |first1=Eun Ryoung |last2=Shi |first2=Ping |last3=Bryant |first3=Jamal |last4=Chen |first4=Jing |last5=Dukhande |first5=Vikas |last6=Gentry |first6=Matthew S. |last7=Jang |first7=HyeIn |last8=Jeoung |first8=Myoungkun |last9=Galperin |first9=Emilia |date=October 2014 |title=HUWE1 Is a Molecular Link Controlling RAF-1 Activity Supported by the Shoc2 Scaffold |journal=Molecular and Cellular Biology |language=en |volume=34 |issue=19 |pages=3579–3593 |doi=10.1128/MCB.00811-14 |issn=0270-7306 |pmc=4187736 |pmid=25022756}}</ref> 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.<ref>{{cite journal | vauthors = 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 | title = Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair | journal = Nature Genetics | volume = 41 | issue = 9 | pages = 1022–6 | date = Sep 2009 | pmid = 19684605 | doi = 10.1038/ng.425 | pmc=2765465}}</ref>

== Interactions ==

SHOC2 has been shown to interact with the catalytic phosphatase subunit PP1C<ref name="A phosphatase holoenzyme comprised">{{cite journal | pmid = 16630891 | doi=10.1016/j.molcel.2006.03.027 | volume=22 | title=A phosphatase holoenzyme {{sic|comprised |hide=y|of}} Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity | date=April 2006 | journal=Mol. Cell | pages=217–30 | vauthors=Rodriguez-Viciana P, Oses-Prieto J, Burlingame A, Fried M, McCormick F }}</ref> and MRAS as well as canonical RAS isoforms (H/K/NRAS).<ref>{{cite journal | pmid = 35768504 | doi=10.1038/s41586-022-04838-3 | volume=609 | title=Structural basis for SHOC2 modulation of RAS signalling | pmc=9452301 | year=2022 | journal=Nature | pages=400–407 | vauthors=Liau NP, Johnson MC, Izadi S, Gerosa L, Hammel M, Bruning JM, Wendorff TJ, Phung W, Hymowitz SG, Sudhamsu J}}</ref><ref>{{cite journal | pmid = 35831509 | doi=10.1038/s41586-022-04928-2 | volume=609 | title=Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex | pmc=9694338 | year=2022 | journal=Nature | pages=408–415 | vauthors=Kwon JJ, Hajian B, Bian Y, Young LC, Amor AJ, Fuller JR, Fraley CV, Sykes AM, So J, Pan J, Baker L, Lee SJ, Wheeler DB, Mayhew DL, Persky NS, Yang X, Root DE, Barsotti AM, Stamford AW, Perry CK, Burgin A, McCormick F, Lemke CT, Hahn WC, Aguirre AJ}}</ref><ref>{{cite journal | pmid = 35830882 | doi=10.1038/s41586-022-05086-1 | volume=609 | title=Structure of the MRAS-SHOC2-PP1C phosphatase complex | pmc=9452295 | year=2022 | journal=Nature | pages=416–423 | vauthors=Hauseman ZJ, Fodor M, Dhembi A, Viscomi J, Egli D, Bleu M, Katz S, Park E, Jang DM, Porter KA, Meili F, Guo H, Kerr G, Mollé S, Velez-Vega C, Beyer KS, Galli GG, Maira SM, Stams T, Clark K, Eck MJ, Tordella L, Thoma CR, King DA}}</ref> The ternary complex SHOC2-RAS-PP1C functions to dephosphorylate an inhibitory phosphorylation site ('S259') on RAF family proteins to enable MAPK signaling.<ref name="A phosphatase holoenzyme comprised"/>

== 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<ref>{{cite journal | pmid = 31213532 | doi=10.1073/pnas.1902658116 | volume=116 | title=SHOC2 complex-driven RAF dimerization selectively contributes to ERK pathway dynamics | pmc=6613145 | year=2019 | journal=Proc Natl Acad Sci U S A | pages=13330–13339 | vauthors=Boned Del RI, Young LC, Sari S, Jones GG, Ringham-Terry B, Hartig N, Rejnowicz E, Lei W, Bhamra A, Surinova S, Rodriguez-Viciana P }}</ref> as well an alternative model proposing post-translational modifications.<ref>{{cite journal | pmid = 25022756 | doi=10.1128/MCB.00811-14 | pmc=4187736 | volume=34 | title=HUWE1 is a molecular link controlling RAF-1 activity supported by the Shoc2 scaffold | year=2014 | journal=Mol Cell Biol | pages=3579–93 | vauthors=Jang ER, Shi P, Bryant J, Chen J, Dukhande V, Gentry MS, Jang H, Jeoung M, Galperin E }}</ref> 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.<ref name=":1" /> 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 == {{reflist}}

== Further reading == {{refbegin | 2}} * {{cite journal | vauthors = Dai P, Xiong WC, Mei L | title = Erbin inhibits RAF activation by disrupting the sur-8-Ras-Raf complex | journal = J. Biol. Chem. | volume = 281 | issue = 2 | pages = 927–33 | year = 2006 | pmid = 16301319 | doi = 10.1074/jbc.M507360200 | doi-access = free }} * {{cite journal | vauthors = Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O | title = 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 | journal = DNA Res. | volume = 5 | issue = 6 | pages = 355–64 | year = 1998 | pmid = 10048485 | doi = 10.1093/dnares/5.6.355 | doi-access = free }} {{refend}}

Category:Proteins