The ShcD signaling adaptor facilitates ligand-independent phosphorylation of the EGF receptor

Wills, Melanie K. B.; Tong, Jiefei; Tremblay, Stéphane; Moran, Michael F.; Jones, Nina

doi:10.1091/mbc.e13-08-0434

Cited by 18 publications

(43 citation statements)

References 52 publications

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“…Our findings further underscore the non-canonical characteristics of ShcD, which may be of particular relevance to the malignancies in which ShcD is overexpressed, including glioma (Wills et al, 2014) and melanoma (Fagiani et al, 2007).…”

Section: Introductionsupporting

confidence: 60%

“…Intriguingly, the AP2 adaptin-binding motif (AD) is conserved across all Shc adaptors except ShcD, and the physiological consequence of this loss has not yet been investigated. We have previously shown that ShcD is an EGFR binding partner that possesses the unique capacity to promote ligand-independent phosphorylation of the receptor on three physiologically relevant sites -Y1068, Y1148 and Y1173 (Wills et al, 2014). This phenomenon was found to require both the intrinsic EGFR kinase, and the PTB domain of ShcD.…”

Section: Introductionmentioning

confidence: 98%

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The ShcD phosphotyrosine adaptor subverts canonical EGF receptor trafficking

Wills

Lau

Jones

2017

Journal of Cell Science

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Shc family signalling adaptors connect activated transmembrane receptors to proximal effectors, and most also contain a sequence involved in clathrin-mediated receptor endocytosis. Notably, this AP2 adaptin-binding motif (AD) is absent from the ShcD (also known as Shc4) homolog, which also uniquely promotes ligand-independent phosphorylation of the epidermal growth factor receptor (EGFR). We now report that cultured cells expressing ShcD exhibit reduced EGF uptake, commensurate with a decrease in EGFR surface presentation. Under basal conditions, ShcD colocalises with the EGFR and facilitates its phosphorylation, ubiquitylation and accumulation in juxtanuclear vesicles identified as Rab11-positive endocytic recycling compartments. Accordingly, ShcD also functions as a constitutive binding partner for the E3 ubiquitin ligase Cbl. EGFR phosphorylation and focal accumulation likewise occur upon ShcD co-expression in U87 glioma cells. Loss of ShcD phosphotyrosine-binding function or insertion of the ShcA AD sequence each restore ligand acquisition through distinct mechanisms. The AD region also contains a nuclear export signal, indicating its multifunctionality. Overall, ShcD appears to possess several molecular permutations that actively govern the EGFR, which may have implications in development and disease.

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Section: Introductionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 98%

The ShcD phosphotyrosine adaptor subverts canonical EGF receptor trafficking

Wills

Lau

Jones

2017

Journal of Cell Science

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“…3). Of note, MIA, S100B, FABP7, and SHC4/RaLP have been previously linked to melanoma 65–68 and glioma 69–71 . Overall, we identified 10 basic cell lineage markers shared between ACC, BBC, melanoma, and Schwann cells that strongly supported our hypothesis on the origin of these three cancers from Schwann cell precursors (FIG.…”

Section: Resultsmentioning

confidence: 93%

Expression Profiling of Clinical Specimens Supports the Existence of Neural Progenitor-Like Stem Cells in Basal Breast Cancers

Panaccione

Guo

Yarbrough

et al. 2017

Clinical Breast Cancer

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To facilitate development of CSC-targeting therapies, we analyzed publicly available breast cancer datasets to identify genes co-expressed with SOX10, a neural crest marker, and PROM1/CD133, a common CSC marker. The conserved SOX10/PROM1 gene signature that we characterized supports the existence in basal breast cancers of SOX10+/CD133+ cells with neural stem-like features exposing clinically relevant CSC markers and signaling networks. Background We previously characterized in salivary adenoid cystic carcinoma (ACC) a novel population of CSC marked by co-expression of two stemness genes, SOX10 and CD133. We also reported that in ACC and basal-like breast carcinoma (BBC), a triple-negative breast cancer subtype, expression of SOX10 similarly demarcates a highly conserved gene signature enriched with neural stem cell genes. Based on these findings, we hypothesized that BBC may be likewise driven by SOX10+/CD133+ cells with neural stem cell properties. Methods To validate our hypothesis on clinical data, we used a novel approach to meta-analysis that merges gene expression data from independent breast cancer studies and ranks genes by statistical significance of their co-expression with the gene of interest. Genes that showed strong association with both CD133/PROM1 and SOX10 were validated across different platforms and datasets and analyzed for enrichment with genes involved in neurogenesis. Results We identified in clinical breast cancer datasets a highly conserved SOX10/PROM1 gene signature that contains neural stem cell markers common for Schwann cells, ACC, BBC, and melanoma. Identification of TRIM2, TRIM29, MPZL2, KCNN4, and VTCN1/B7-H4 within this signature provides insight into molecular mechanisms of CSC maintenance. Conclusion Our results suggest that BBC is driven by SOX10+/CD133+ cells that express NSC-specific markers and share molecular similarities with CSC of neural crest origin. Our study provides clinically relevant information on possible drivers of these cells that may facilitate development of CSC-targeting therapies against this cancer distinguished with poor prognosis and resistance to conventional therapies.

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“…Sch4 is maximally expressed at stages IIÀIII, and the docking protein is concentrated at the plasma membrane, where it facilitates ligand-independent phosphorylation of the epidermal growth factor (EGF) receptor, which is also expressed by Sertoli cells [69,70]. This phosphorylation allows for cross talk between different receptor systems, leading us to suggest that the stage-dependent increase in SCH4 allows the efficient integration of multiple signaling pathways in Sertoli cells [71].…”

Section: A Kinase Anchoring Proteinsmentioning

confidence: 99%

“…Maximal expression of these genes occurs at stages VIIc,d, VIII, and IXÀXI, respectively. Maff is noteworthy because its protein product suppresses EGF-driven gene transcription and because its stage-specific pattern of expression is the opposite of that of Sch4, which facilitates ligand-independent phosphorylation and activation of the EGF -receptor [69]. Two transcriptional repressors complete this list: HOP homeobox (Hopx) and zinc finger homeobox 3 (Zfhx3), which are maximally expressed at stages 298 Sertoli Cell Biology VI and VIIc,d, respectively.…”

Section: Transcriptional Activators and Repressorsmentioning

confidence: 99%