{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nShcD (also known as Shc4) is a member of the Shc adaptor protein family that is expressed in adult brain and skeletal muscle, where it plays a critical role at the neuromuscular junction. Here, its phosphotyrosine‐binding (PTB) domain enables association with receptor tyrosine kinases such as the muscle‐specific kinase (MuSK), promoting early tyrosine phosphorylation events that are essential for the clustering and activation of acetylcholine receptors and proper synaptic transmission."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in neuromuscular signaling, ShcD exerts noncanonical regulation of growth factor receptors. It functions as a potent modulator of the epidermal growth factor receptor (EGFR) signaling cascade by promoting ligand‐independent hyperphosphorylation of specific EGFR tyrosine residues and diminishing receptor endocytosis through reduced EGF uptake. These actions are linked to altered receptor trafficking and ubiquitylation, underscoring a unique regulatory mechanism that distinguishes ShcD from other Shc family members."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn neuronal contexts, ShcD also interacts with neurotrophin receptors. It associates in a kinase-dependent manner with receptors such as TrkB—and by extension TrkC as indicated by ongoing investigations—and with additional receptors like Ret and TrkA. These interactions facilitate the recruitment of effector proteins including Grb2, thereby modulating downstream mitogen-activated protein kinase (MAPK/Erk) signaling. Notably, ShcD can even suppress distal MAPK activation, pointing to a finely balanced role in neurotrophic signal transduction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nShcD’s multifaceted signaling functions extend into cancer pathobiology, where its dysregulation promotes tumor progression and invasion. In melanoma, overexpression of ShcD contributes to enhanced cellular migration and invasion; intriguingly, ShcD undergoes nuclear translocation—mediated by a defined nuclear export signal within its CH2 domain—and can associate with DNA to affect transcriptional programs that may confer resistance to oxidative stress. In gliomas, ShcD cooperates with the Tie2 receptor to stimulate invadopodia formation and matrix degradation, facilitating diffuse tumor infiltration. Similarly, in triple-negative breast cancer, upregulated SHC4 interacts with Src—via a critical CH2 domain sequence—to maintain Src autophosphorylation and drive β-catenin activation, thereby upregulating downstream targets such as CD44 and MMP7."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nina Jones, W Rod Hardy, Matthew B Friese, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Analysis of a Shc family adaptor protein, ShcD/Shc4, that associates with muscle-specific kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00184-07"}], "href": "https://doi.org/10.1128/MCB.00184-07"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17452444"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17452444"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Melanie K B Wills, Jiefei Tong, Sylvie L Tremblay, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ShcD signaling adaptor facilitates ligand-independent phosphorylation of the EGF receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.E13-08-0434"}], "href": "https://doi.org/10.1091/mbc.E13-08-0434"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24430869"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24430869"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Melanie K B Wills, Hayley R Lau, Nina Jones "}, {"type": "b", "children": [{"type": "t", "text": "The ShcD phosphotyrosine adaptor subverts canonical EGF receptor trafficking."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.198903"}], "href": "https://doi.org/10.1242/jcs.198903"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28724758"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28724758"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yuangang You, Weiqi Li, Yanhua Gong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ShcD interacts with TrkB via its PTB and SH2 domains and regulates BDNF-induced MAPK activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMB Rep (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.5483/bmbrep.2010.43.7.485"}], "href": "https://doi.org/10.5483/bmbrep.2010.43.7.485"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20663410"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20663410"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Melanie K B Wills, Ava Keyvani Chahi, Hayley R Lau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Signaling adaptor ShcD suppresses extracellular signal-regulated kinase (Erk) phosphorylation distal to the Ret and Trk neurotrophic receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M116.770511"}], "href": "https://doi.org/10.1074/jbc.M116.770511"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28213521"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28213521"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yuan-gang You, Wei-qi Li, Bin Yin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[ShcD interacts with TrkC through its PTB and SH2 domains]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Zhongguo Yi Xue Ke Xue Yuan Xue Bao (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3881/j.issn.1000-503X.2009.06.013"}], "href": "https://doi.org/10.3881/j.issn.1000-503X.2009.06.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20078941"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20078941"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Samrein B M Ahmed, Sally A Prigent "}, {"type": "b", "children": [{"type": "t", "text": "A nuclear export signal and oxidative stress regulate ShcD subcellular localisation: a potential role for ShcD in the nucleus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2013.09.003"}], "href": "https://doi.org/10.1016/j.cellsig.2013.09.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24036217"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24036217"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Manali Tilak, Begüm Alural, Sarah E Wismer, et al. 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