A Leucine-Rich Repeat Protein Provides a SHOC2 the RAS Circuit: a Structure-Function Perspective

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2021 Feb 2

PMID 33526449

Citations 14

Authors

Jason J Kwon

William C Hahn

Affiliations

Soon will be listed here.

Abstract

SHOC2 is a prototypical leucine-rich repeat protein that promotes downstream receptor tyrosine kinase (RTK)/RAS signaling and plays important roles in several cellular and developmental processes. Gain-of-function germ line mutations of SHOC2 drive the RASopathy Noonan-like syndrome, and SHOC2 mediates adaptive resistance to mitogen-activated protein kinase (MAPK) inhibitors. Similar to many scaffolding proteins, SHOC2 facilitates signal transduction by enabling proximal protein interactions and regulating the subcellular localization of its binding partners. Here, we review the structural features of SHOC2 that mediate its known functions, discuss these elements in the context of various binding partners and signaling pathways, and highlight areas of SHOC2 biology where a consensus view has not yet emerged.

Citing Articles

Noonan syndrome and Noonan-like syndrome with loose anagen hair: rare phenotypes may emerge during follow-up.

Liu Z, Lai J, Song F Transl Pediatr. 2024; 13(7):1161-1168.

PMID: 39144424 PMC: 11320002. DOI: 10.21037/tp-24-113.

RAS and SHOC2 Roles in RAF Activation and Therapeutic Considerations.

Bonsor D, Simanshu D Annu Rev Cancer Biol. 2024; 8:97-113.

PMID: 38882927 PMC: 11178279. DOI: 10.1146/annurev-cancerbio-062822-030450.

The expression of congenital Shoc2 variants induces AKT-dependent crosstalk activation of the ERK1/2 pathway.

Wilson P, Abdelmoti L, Gao T, Galperin E Hum Mol Genet. 2024; 33(18):1592-1604.

PMID: 38881369 PMC: 11373329. DOI: 10.1093/hmg/ddae100.

KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination.

Rosell R, Jantus-Lewintre E, Cao P, Cai X, Xing B, Ito M Cell Commun Signal. 2024; 22(1):324.

PMID: 38867255 PMC: 11167791. DOI: 10.1186/s12964-024-01667-x.

Exploiting bacterial effector proteins to uncover evolutionarily conserved antiviral host machinery.

Embry A, Baggett N, Heisler D, White A, de Jong M, Kocsis B PLoS Pathog. 2024; 20(5):e1012010.

PMID: 38753575 PMC: 11098378. DOI: 10.1371/journal.ppat.1012010.

References

Hanson P, Whiteheart S . AAA+ proteins: have engine, will work. Nat Rev Mol Cell Biol. 2005; 6(7):519-29. DOI: 10.1038/nrm1684. View

Yi J, Chen M, Wu X, Yang X, Xu T, Zhuang Y . Endothelial SUR-8 acts in an ERK-independent pathway during atrioventricular cushion development. Dev Dyn. 2010; 239(7):2005-13. PMC: 3138404. DOI: 10.1002/dvdy.22343. View

Kobayashi T, Aoki Y, Niihori T, Cave H, Verloes A, Okamoto N . Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. Hum Mutat. 2010; 31(3):284-94. DOI: 10.1002/humu.21187. View

Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D . RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011; 11(11):761-74. PMC: 3632399. DOI: 10.1038/nrc3106. View

Cordeddu V, Di Schiavi E, Pennacchio L, Maayan A, Sarkozy A, Fodale V . Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009; 41(9):1022-6. PMC: 2765465. DOI: 10.1038/ng.425. View

Bilder D, Birnbaum D, Borg J, Bryant P, Huigbretse J, Jansen E . Collective nomenclature for LAP proteins. Nat Cell Biol. 2000; 2(7):E114. DOI: 10.1038/35017119. View

Jang H, Oakley E, Forbes-Osborne M, Kesler M, Norcross R, Morris A . Hematopoietic and neural crest defects in zebrafish shoc2 mutants: a novel vertebrate model for Noonan-like syndrome. Hum Mol Genet. 2018; 28(3):501-514. PMC: 6337701. DOI: 10.1093/hmg/ddy366. View

Matsunaga-Udagawa R, Fujita Y, Yoshiki S, Terai K, Kamioka Y, Kiyokawa E . The scaffold protein Shoc2/SUR-8 accelerates the interaction of Ras and Raf. J Biol Chem. 2010; 285(10):7818-26. PMC: 2844225. DOI: 10.1074/jbc.M109.053975. View

Sebolt-Leopold J, Herrera R . Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004; 4(12):937-47. DOI: 10.1038/nrc1503. View

10.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

11.

Lavoie H, Therrien M . Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol. 2015; 16(5):281-98. DOI: 10.1038/nrm3979. View

12.

Samatar A, Poulikakos P . Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov. 2014; 13(12):928-42. DOI: 10.1038/nrd4281. View

13.

Hervieu A, Kermorgant S . The Role of PI3K in Met Driven Cancer: A Recap. Front Mol Biosci. 2018; 5:86. PMC: 6207648. DOI: 10.3389/fmolb.2018.00086. View

14.

Choi J, Troyanovsky R, Indra I, Mitchell B, Troyanovsky S . Scribble, Erbin, and Lano redundantly regulate epithelial polarity and apical adhesion complex. J Cell Biol. 2019; 218(7):2277-2293. PMC: 6605793. DOI: 10.1083/jcb.201804201. View

15.

Sauer R, Baker T . AAA+ proteases: ATP-fueled machines of protein destruction. Annu Rev Biochem. 2011; 80:587-612. DOI: 10.1146/annurev-biochem-060408-172623. View

16.

Nateri A, Riera-Sans L, Da Costa C, Behrens A . The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling. Science. 2004; 303(5662):1374-8. DOI: 10.1126/science.1092880. View

17.

Zhao X, Heng J, Guardavaccaro D, Jiang R, Pagano M, Guillemot F . The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nat Cell Biol. 2008; 10(6):643-53. PMC: 2680438. DOI: 10.1038/ncb1727. View

18.

Kaduwal S, Jeong W, Park J, Lee K, Lee Y, Jeon S . Sur8/Shoc2 promotes cell motility and metastasis through activation of Ras-PI3K signaling. Oncotarget. 2015; 6(32):33091-105. PMC: 4741751. DOI: 10.18632/oncotarget.5173. View

19.

Janes M, Zhang J, Li L, Hansen R, Peters U, Guo X . Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. Cell. 2018; 172(3):578-589.e17. DOI: 10.1016/j.cell.2018.01.006. View

20.

Komatsuzaki S, Aoki Y, Niihori T, Okamoto N, Hennekam R, Hopman S . Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. J Hum Genet. 2010; 55(12):801-9. DOI: 10.1038/jhg.2010.116. View