A Novel<i>SHOC2</i>Variant in Rasopathy

Hannig, Vickie; Jeoung, Myoungkun; Jang, Eun Ryoung; Phillips, John A.; Galperin, Emilia

doi:10.1002/humu.22634

Cited by 28 publications

(44 citation statements)

References 19 publications

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“…Ras is a small GTPase with critical signaling functions in the cell, including the MAPK signaling cascade. Although best-known for its role in cancer due to acquired somatic mutations, dysregulation of genes in the Ras/MAPK pathway in human development causes disorders including neurofibromatosis type 1 (NF1: NF1 [33]), Noonan syndrome and Noonan syndrome with multiple lentigines[34] (NS: CBL [35], BRAF , KRAS [36], LZTR1 [37], NRAS [38,39], PTPN11 [40], RAF1 [41], RASA2 [42], RIT1 [43], SHOC2 [44–46], SOS1 [47,48], and SOS2 [37]), Gingival fibromatosis 1 ( SOS1 [49,50]), Capillary malformation-arteriovenous malformation (CM-AVM) ( RASA1 [51,52]), Costello syndrome (CS: HRAS [53]), Cardio-facio-cutaneous syndrome (CFC[54]: BRAF , MAP2K1 , MAP2K2 , KRAS ), and NF1-like syndrome ( SPRED1 [55]). Many of these syndromes share craniofacial dysmorphology, cardiac malformations and cutaneous, musculoskeletal and ocular abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

et al. 2017

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Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10−16), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway.

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Section: Introductionmentioning

confidence: 99%

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

et al. 2017

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“…This evolutionarily well-conserved protein is essential for normal development [19–21]. Loss of Shoc2 in mammalian cultured cells and C. elegans leads to a dramatic decrease in ERK1/2 activity [17, 22, 23].…”

Section: Introductionmentioning

confidence: 99%

Shoc2-tranduced ERK1/2 motility signals — Novel insights from functional genomics

Jeoung

Jang

Liu

et al. 2016

Cellular Signalling

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The extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway plays a central role in defining various cellular fates. Scaffold proteins modulating ERK1/2 activity control growth factor signals transduced by the pathway. Here, we analyzed signals transduced by Shoc2, a critical positive modulator of ERK1/2 activity. We found that loss of Shoc2 results in impaired cell motility and delays cell attachment. As ERKs control cellular fates by stimulating transcriptional response, we hypothesized that the mechanisms underlying changes in cell adhesion could be revealed by assessing the changes in transcription of Shoc2-depleted cells. Using quantitative RNA-seq analysis, we identified 853 differentially expressed transcripts. Characterization of the differentially expressed genes showed that Shoc2 regulates the pathway at several levels, including expression of genes controlling cell motility, adhesion, crosstalk with the transforming growth factor beta (TGFβ) pathway, and expression of transcription factors. To understand the mechanisms underlying delayed attachment of cells depleted of Shoc2, changes in expression of the protein of extracellular matrix (lectin galactoside-binding soluble 3-binding protein; LGALS3BP) were functionally analyzed. We demonstrated that delayed adhesion of the Shoc2-depleted cells is a result of attenuated expression and secretion of LGALS3BP. Together our results suggest that Shoc2 regulates cell motility by modulating ERK1/2 signals to cell adhesion.

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“…The physiological significance of Shoc2 was underlined by studies showing that a mouse endothelial Shoc2 knockout leads to embryonic lethality (Yi et al, 2010). Mutations in Shoc2 affecting either Shoc2 localization (Cordeddu et al, 2009) or the assembly of the Shoc2 scaffold complex (Hannig et al, 2014) result in RASopathy -a congenital syndrome with a spectrum of overlapping symptoms, further emphasizing the importance of Shoc2. We have previously demonstrated that upon activation of the ERK1/2 pathway, Shoc2 translocates from the cytosol to late endosomes and/or multivesicular bodies (MVBs), possibly as part of the spatio-temporal regulation of signaling through the Ras-RAF-1 module (Galperin et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Spatial control of Shoc2 scaffold-mediated ERK1/2 signaling requires remodeling activity of the ATPase PSMC5

Jang

Shi

et al. 2015

Journal of Cell Science

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The scaffold protein Shoc2 accelerates activity of the ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1) pathway. Mutations in Shoc2 result in Noonan-like RASopathy, a developmental disorder with a wide spectrum of symptoms. The amplitude of the ERK1/2 signals transduced through the complex is fine-tuned by the HUWE1-mediated ubiquitylation of Shoc2 and its signaling partner RAF-1. Here, we provide a mechanistic basis of how ubiquitylation of Shoc2 and RAF-1 is controlled. We demonstrate that the newly identified binding partner of Shoc2, the (AAA+) ATPase PSMC5, triggers translocation of Shoc2 to endosomes. At the endosomes, PSMC5 displaces the E3 ligase HUWE1 from the scaffolding complex to attenuate ubiquitylation of Shoc2 and RAF-1. We show that a RASopathy mutation that changes the subcellular distribution of Shoc2 leads to alterations in Shoc2 ubiquitylation due to the loss of accessibility to PSMC5. In summary, our results demonstrate that PSMC5 is a new and important player involved in regulating ERK1/2 signal transmission through the remodeling of Shoc2 scaffold complex in a spatially-defined manner.

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A NovelSHOC2Variant in Rasopathy

Cited by 28 publications

References 19 publications

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

Shoc2-tranduced ERK1/2 motility signals — Novel insights from functional genomics

Spatial control of Shoc2 scaffold-mediated ERK1/2 signaling requires remodeling activity of the ATPase PSMC5

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