{"gene":"SHC2","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":1998,"finding":"Sck (SHC2) interacts with the VEGF receptor KDR (KDR/VEGFR2) via its SH2 domain in a phosphorylation-dependent manner, with Y1175 of KDR identified as the major binding site; the PTB domain of Sck does not bind KDR or Flt-1.","method":"Yeast two-hybrid screen of human brain cDNA library with KDR cytoplasmic domain as bait; site-directed mutagenesis of KDR; SH2/PTB domain deletion constructs","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid identification followed by site-directed mutagenesis of binding site and domain deletion analysis, replicated independently in a second lab (PMID:10749680)","pmids":["9790910","10749680"],"is_preprint":false},{"year":2000,"finding":"Sck (SHC2) forms a phosphorylation-dependent complex with the VEGF receptor KDR at tyrosine-1175 in VEGF-stimulated endothelial cells; the SH2 domain (not PTB domain) of Sck mediates this interaction; chimeric Sck/Shc SH2 domain fusion proteins attenuate VEGF-induced MAPK activation.","method":"Co-immunoprecipitation from VEGF-stimulated PAE cells; recombinant SH2 domain binding to phosphotyrosine 1175-derived synthetic peptide; dominant-negative chimeric protein experiments in endothelial cells","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with phosphorylation-site mutant receptor, recombinant domain-peptide binding, and functional chimeric protein experiments in same study; independently confirmed by PMID:9790910","pmids":["10749680"],"is_preprint":false},{"year":2002,"finding":"Sck (SHC2) is expressed in vascular endothelial cells and is recruited to KDR tyrosine-1175 upon VEGF stimulation, leading to enhanced Sck tyrosine phosphorylation; Sck participates in VEGF-induced signal transduction.","method":"RT-PCR, Western blot, immunohistochemistry for Sck expression; co-immunoprecipitation from VEGF-treated HUVE cells and PAE cells expressing KDR Y1175 mutant; recombinant SH2 domain peptide-binding assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with phosphorylation-site mutant receptor, replicated across multiple cell types; consistent with prior independent findings (PMIDs 9790910, 10749680)","pmids":["12214271"],"is_preprint":false},{"year":1998,"finding":"N-Shc and Sck (SHC2) have distinct signaling functions in neurons: N-Shc is a higher-affinity adapter in NGF/BDNF signaling; Sck (but not N-Shc) forms a complex with a 135 kDa phosphoprotein (pp135) highly phosphorylated by v-Src; N-Shc (but not Sck) is efficiently phosphorylated by activated Src.","method":"Immunoprecipitation experiments in neuronal cells; NGF/BDNF stimulation assays; v-Src co-expression experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP/immunoprecipitation experiments distinguishing N-Shc and Sck functions, single lab but multiple conditions tested","pmids":["9507002"],"is_preprint":false},{"year":2001,"finding":"The full-length Sck/ShcB (p68) is more efficiently tyrosine-phosphorylated upon EGF treatment than the previously-analyzed CH2-deleted form; Sck specifically interacts with a 135 kDa phosphoprotein (pp135) through its SH2 domain following membrane depolarization, and this interaction is reduced by Src kinase inhibitors.","method":"Genomic organization analysis; Western blot for EGF-induced phosphorylation; co-immunoprecipitation with SH2 domain; Src kinase inhibitor treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — domain-specific Co-IP with pharmacological inhibitor validation; single lab with multiple methods","pmids":["11409899"],"is_preprint":false},{"year":2000,"finding":"ShcB (SHC2)-deficient mice exhibit a loss of peptidergic and nonpeptidergic nociceptive sensory neurons, demonstrating a unique role for ShcB in survival/maturation of nociceptive neurons; loss of both ShcB and ShcC causes significant loss of neurons in the superior cervical ganglia, indicating overlapping functions in sympathetic neuron development.","method":"Generation of ShcB and ShcC null mice; histological analysis of peripheral nervous system neurons in single and double knockout animals","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mice with defined cellular phenotypes, single/double KO comparison distinguishing unique and overlapping functions; single lab but multiple genetic conditions tested","pmids":["11163269"],"is_preprint":false},{"year":2002,"finding":"ShcB (SHC2) and ShcC bind Trk receptors (TrkA at Y499, TrkB at Y515) via their N-terminal PTB domain in a phosphotyrosine-dependent manner, become tyrosine-phosphorylated in response to neurotrophin stimulation, and enhance MAPK activation in Trk-expressing cells; neurotrophin treatment of primary cortical neurons stimulates ShcB/ShcC–Trk interaction and ShcB/ShcC tyrosine phosphorylation in vivo.","method":"Co-immunoprecipitation in Trk-expressing cells and primary cortical neurons; phosphotyrosine-dependent binding assays; MAPK activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP in both heterologous cells and primary neurons, phosphotyrosine-dependence established, functional MAPK readout; single lab with multiple orthogonal methods","pmids":["12006576"],"is_preprint":false},{"year":2015,"finding":"Sck (SHC2) was identified as a downstream mediator indispensable for CD95-induced cell cycle progression in pancreatic ductal adenocarcinoma; CD95 drives tumour growth and metastasis via Sck.","method":"In silico RNA profile analysis; mechanistic follow-up in PDAC cancer stem cells and xenograft/syngeneic mouse models; pharmacological inhibition of CD95","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional placement of Sck downstream of CD95 in cancer cell lines and in vivo models, but mechanistic detail of Sck's biochemical role in cell cycle is limited in the abstract","pmids":["25613377"],"is_preprint":false},{"year":2020,"finding":"ShcB (SHC2) knockout mice show defects in cerebellar-dependent motor function and impaired long-term depression (LTD) at cerebellar synapses, accompanied by impaired intracellular Ca2+ release from ER; the content of intracellular Ca2+ store and SERCA activity are decreased in ShcB-deficient cerebellum; ectopic re-expression of ShcB in KO Purkinje cells restores Ca2+ release and SERCA-dependent Ca2+ uptake.","method":"ShcB knockout mice; behavioral tests; cerebellar LTD electrophysiology; Ca2+ imaging; SERCA activity assay; rescue by ShcB re-expression","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular and molecular phenotype, rescue experiment establishing causality, multiple orthogonal methods (electrophysiology, Ca2+ imaging, biochemical SERCA assay); single lab","pmids":["32879382"],"is_preprint":false},{"year":2021,"finding":"ShcB (SHC2) acts downstream of TrkB in chondrocytes; silencing ShcB reverses the effects of TrkB overexpression on cell migration, angiogenesis, tube formation, and VEGF secretion in IL-1β-stimulated chondrocytes, placing ShcB as a required downstream effector in the TrkB/ShcB signaling axis.","method":"shRNA knockdown of ShcB and TrkB in chondrocytes; overexpression rescue; cell migration, invasion, proliferation, tube formation assays; VEGF ELISA; Western blot","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — epistasis by knockdown/overexpression in cell lines, multiple functional readouts, single lab","pmids":["34107348"],"is_preprint":false}],"current_model":"SHC2 (ShcB/Sck) is a phosphotyrosine adapter protein expressed predominantly in neurons and endothelial cells that binds activated receptor tyrosine kinases (Trk receptors at specific phosphotyrosines via its PTB domain; KDR/VEGFR2 at Y1175 via its SH2 domain) to scaffold downstream signaling including MAPK activation; in neurons it is required for nociceptive and sympathetic neuron survival/development, and in cerebellar Purkinje cells it maintains ER Ca2+ store integrity by supporting SERCA activity, thereby enabling synaptic long-term depression; in cancer contexts it acts downstream of CD95 to promote cell cycle progression and metastasis."},"narrative":{"mechanistic_narrative":"SHC2 (ShcB/Sck) is a phosphotyrosine adapter protein that couples activated receptor tyrosine kinases to downstream MAPK signaling and governs neuronal survival and function [PMID:12006576, PMID:11163269]. It engages receptors through two distinct modular interfaces: its SH2 domain binds the VEGF receptor KDR/VEGFR2 at phosphotyrosine-1175 in a phosphorylation-dependent manner upon VEGF stimulation in endothelial cells, while its PTB domain binds Trk receptors (TrkA at Y499, TrkB at Y515) following neurotrophin stimulation [PMID:10749680, PMID:12006576]. Receptor engagement drives SHC2 tyrosine phosphorylation and enhances MAPK activation, and dominant-negative SH2 chimeras attenuate VEGF-induced MAPK signaling [PMID:10749680, PMID:12006576]. In the nervous system, SHC2 is required for survival and maturation of nociceptive sensory neurons and, redundantly with ShcC, for sympathetic neuron development [PMID:11163269]. In cerebellar Purkinje cells it maintains ER Ca2+ store content and SERCA activity, an activity required for synaptic long-term depression and cerebellar motor function, as shown by knockout phenotypes rescued by ShcB re-expression [PMID:32879382]. SHC2 also acts as a required downstream effector in disease contexts, mediating CD95-driven cell cycle progression and metastasis in pancreatic adenocarcinoma and TrkB-driven angiogenic responses in chondrocytes [PMID:25613377, PMID:34107348].","teleology":[{"year":1998,"claim":"Established that SHC2 is a receptor-specific adapter by defining its physical link to the VEGF receptor and mapping the interaction interface, answering how SHC2 connects to receptor tyrosine kinases.","evidence":"Yeast two-hybrid with KDR cytoplasmic domain, site-directed mutagenesis, and SH2/PTB deletion constructs","pmids":["9790910","10749680"],"confidence":"High","gaps":["Did not establish downstream signaling consequences","Functional role in endothelial cells not yet tested"]},{"year":1998,"claim":"Distinguished SHC2 from the related neuronal adapter N-Shc, showing SHC2 has a unique binding partner (a 135 kDa phosphoprotein) and distinct kinase relationships, establishing functional non-redundancy among Shc family members.","evidence":"Immunoprecipitation in neuronal cells with NGF/BDNF stimulation and v-Src co-expression","pmids":["9507002"],"confidence":"Medium","gaps":["Identity of the 135 kDa phosphoprotein unresolved","Single-lab Co-IP without reciprocal validation"]},{"year":2000,"claim":"Confirmed in physiological endothelial cells that the SHC2-KDR interaction occurs at Y1175 and contributes functionally to VEGF signaling, moving the interaction from yeast two-hybrid to native receptor signaling.","evidence":"Co-IP from VEGF-stimulated PAE cells, recombinant SH2-phosphopeptide binding, and dominant-negative chimera experiments","pmids":["10749680"],"confidence":"High","gaps":["Downstream effectors recruited by SHC2 at KDR not identified","MAPK attenuation shown only with artificial chimera"]},{"year":2000,"claim":"Defined the in vivo neuronal requirement for SHC2, answering whether the adapter is essential for development by revealing nociceptive neuron loss and redundancy with ShcC in sympathetic neurons.","evidence":"Single and double ShcB/ShcC knockout mice with histological analysis of peripheral neurons","pmids":["11163269"],"confidence":"High","gaps":["Receptor and signaling pathway driving the survival defect not yet linked","Molecular mechanism of survival support unresolved"]},{"year":2001,"claim":"Refined SHC2 biochemistry by showing the full-length p68 isoform is the efficiently phosphorylated form and that its SH2-mediated pp135 interaction is Src-dependent and depolarization-regulated.","evidence":"Genomic organization analysis, EGF-induced phosphorylation Western blots, SH2 Co-IP with Src inhibitor treatment","pmids":["11409899"],"confidence":"Medium","gaps":["pp135 identity remains unknown","Functional consequence of the depolarization-dependent interaction untested"]},{"year":2002,"claim":"Connected SHC2's neuronal role to a specific receptor class, showing PTB-domain binding to Trk receptors at defined phosphotyrosines drives neurotrophin-stimulated MAPK activation in primary neurons.","evidence":"Co-IP in Trk-expressing cells and primary cortical neurons, phosphotyrosine-dependent binding, and MAPK activation assays","pmids":["12006576"],"confidence":"High","gaps":["Link between Trk binding and the in vivo neuronal survival phenotype not directly demonstrated","Downstream effectors beyond MAPK not mapped"]},{"year":2002,"claim":"Solidified SHC2 expression in vascular endothelium and its VEGF-induced recruitment to KDR Y1175, integrating expression, localization, and signaling for the endothelial arm.","evidence":"RT-PCR, Western blot, immunohistochemistry, and Co-IP from VEGF-treated HUVEC and PAE cells","pmids":["12214271"],"confidence":"High","gaps":["Specific endothelial functional output of SHC2 signaling not quantified","Downstream adapters recruited by SHC2 unresolved"]},{"year":2015,"claim":"Extended SHC2 into disease biology by placing it as an indispensable downstream mediator of CD95-driven cell cycle progression and metastasis in pancreatic cancer.","evidence":"In silico RNA profiling, PDAC cancer stem cell and xenograft/syngeneic models, and pharmacological CD95 inhibition","pmids":["25613377"],"confidence":"Medium","gaps":["Biochemical mechanism linking SHC2 to cell cycle progression not defined","Direct CD95-SHC2 physical interaction not shown"]},{"year":2020,"claim":"Revealed an unexpected non-canonical role for SHC2 in cerebellar Purkinje cells, where it maintains ER Ca2+ stores via SERCA activity to enable long-term depression, established causally by rescue.","evidence":"ShcB knockout mice with behavior, cerebellar LTD electrophysiology, Ca2+ imaging, SERCA assay, and re-expression rescue","pmids":["32879382"],"confidence":"High","gaps":["Molecular link between adapter function and SERCA regulation unknown","Whether this role requires receptor tyrosine kinase input untested"]},{"year":2021,"claim":"Placed SHC2 as a required downstream effector of TrkB in chondrocytes, showing it transmits TrkB-driven migration, angiogenesis, and VEGF secretion signals.","evidence":"shRNA knockdown and overexpression epistasis in IL-1β-stimulated chondrocytes with functional and VEGF ELISA readouts","pmids":["34107348"],"confidence":"Medium","gaps":["Direct TrkB-SHC2 interaction in chondrocytes not biochemically shown","Single-lab cell-line epistasis without in vivo confirmation"]},{"year":null,"claim":"The molecular identity of the SHC2-specific pp135 partner and the biochemical mechanism by which SHC2 controls SERCA activity and cell cycle progression remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["pp135 has not been identified","No mechanistic link between SHC2 adapter function and SERCA/ER Ca2+ regulation","No structural model of SHC2 receptor complexes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[8]}],"complexes":[],"partners":["KDR","NTRK1","NTRK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P98077","full_name":"SHC-transforming protein 2","aliases":["Protein Sck","SHC-transforming protein B","Src homology 2 domain-containing-transforming protein C2","SH2 domain protein C2"],"length_aa":582,"mass_kda":61.9,"function":"Signaling adapter that couples activated growth factor receptors to signaling pathway in neurons. Involved in the signal transduction pathways of neurotrophin-activated Trk receptors in cortical neurons (By similarity)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P98077/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SHC2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SHC2","total_profiled":1310},"omim":[{"mim_id":"611969","title":"MOB KINASE ACTIVATOR 2; MOB2","url":"https://www.omim.org/entry/611969"},{"mim_id":"610278","title":"PLATELET ENDOTHELIAL AGGREGATION RECEPTOR 1; PEAR1","url":"https://www.omim.org/entry/610278"},{"mim_id":"605217","title":"SHC TRANSFORMING PROTEIN 2; SHC2","url":"https://www.omim.org/entry/605217"},{"mim_id":"146500","title":"MULTIPLE SYSTEM ATROPHY 1, SUSCEPTIBILITY TO; MSA1","url":"https://www.omim.org/entry/146500"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":100.4}],"url":"https://www.proteinatlas.org/search/SHC2"},"hgnc":{"alias_symbol":["SLI","SCK","SHCB"],"prev_symbol":[]},"alphafold":{"accession":"P98077","domains":[{"cath_id":"2.30.29.30","chopping":"144-193_202-308","consensus_level":"high","plddt":88.5683,"start":144,"end":308},{"cath_id":"3.30.505.10","chopping":"480-578","consensus_level":"high","plddt":84.9528,"start":480,"end":578}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P98077","model_url":"https://alphafold.ebi.ac.uk/files/AF-P98077-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P98077-F1-predicted_aligned_error_v6.png","plddt_mean":61.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SHC2","jax_strain_url":"https://www.jax.org/strain/search?query=SHC2"},"sequence":{"accession":"P98077","fasta_url":"https://rest.uniprot.org/uniprotkb/P98077.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P98077/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P98077"}},"corpus_meta":[{"pmid":"10635327","id":"PMC_10635327","title":"Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1.","date":"1999","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/10635327","citation_count":837,"is_preprint":false},{"pmid":"9851973","id":"PMC_9851973","title":"c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor.","date":"1998","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/9851973","citation_count":711,"is_preprint":false},{"pmid":"7652556","id":"PMC_7652556","title":"Similarity of sli-1, a regulator of vulval development in C. elegans, to the mammalian proto-oncogene c-cbl.","date":"1995","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/7652556","citation_count":276,"is_preprint":false},{"pmid":"7789760","id":"PMC_7789760","title":"sli-1, a negative regulator of let-23-mediated signaling in C. elegans.","date":"1995","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7789760","citation_count":128,"is_preprint":false},{"pmid":"11163269","id":"PMC_11163269","title":"The mammalian ShcB and ShcC phosphotyrosine docking proteins function in the maturation of sensory and sympathetic neurons.","date":"2000","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/11163269","citation_count":89,"is_preprint":false},{"pmid":"9507002","id":"PMC_9507002","title":"N-Shc and Sck, two neuronally expressed Shc adapter homologs. 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interacts with the VEGF receptor KDR (KDR/VEGFR2) via its SH2 domain in a phosphorylation-dependent manner, with Y1175 of KDR identified as the major binding site; the PTB domain of Sck does not bind KDR or Flt-1.\",\n      \"method\": \"Yeast two-hybrid screen of human brain cDNA library with KDR cytoplasmic domain as bait; site-directed mutagenesis of KDR; SH2/PTB domain deletion constructs\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid identification followed by site-directed mutagenesis of binding site and domain deletion analysis, replicated independently in a second lab (PMID:10749680)\",\n      \"pmids\": [\"9790910\", \"10749680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Sck (SHC2) forms a phosphorylation-dependent complex with the VEGF receptor KDR at tyrosine-1175 in VEGF-stimulated endothelial cells; the SH2 domain (not PTB domain) of Sck mediates this interaction; chimeric Sck/Shc SH2 domain fusion proteins attenuate VEGF-induced MAPK activation.\",\n      \"method\": \"Co-immunoprecipitation from VEGF-stimulated PAE cells; recombinant SH2 domain binding to phosphotyrosine 1175-derived synthetic peptide; dominant-negative chimeric protein experiments in endothelial cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with phosphorylation-site mutant receptor, recombinant domain-peptide binding, and functional chimeric protein experiments in same study; independently confirmed by PMID:9790910\",\n      \"pmids\": [\"10749680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Sck (SHC2) is expressed in vascular endothelial cells and is recruited to KDR tyrosine-1175 upon VEGF stimulation, leading to enhanced Sck tyrosine phosphorylation; Sck participates in VEGF-induced signal transduction.\",\n      \"method\": \"RT-PCR, Western blot, immunohistochemistry for Sck expression; co-immunoprecipitation from VEGF-treated HUVE cells and PAE cells expressing KDR Y1175 mutant; recombinant SH2 domain peptide-binding assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with phosphorylation-site mutant receptor, replicated across multiple cell types; consistent with prior independent findings (PMIDs 9790910, 10749680)\",\n      \"pmids\": [\"12214271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"N-Shc and Sck (SHC2) have distinct signaling functions in neurons: N-Shc is a higher-affinity adapter in NGF/BDNF signaling; Sck (but not N-Shc) forms a complex with a 135 kDa phosphoprotein (pp135) highly phosphorylated by v-Src; N-Shc (but not Sck) is efficiently phosphorylated by activated Src.\",\n      \"method\": \"Immunoprecipitation experiments in neuronal cells; NGF/BDNF stimulation assays; v-Src co-expression experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP/immunoprecipitation experiments distinguishing N-Shc and Sck functions, single lab but multiple conditions tested\",\n      \"pmids\": [\"9507002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The full-length Sck/ShcB (p68) is more efficiently tyrosine-phosphorylated upon EGF treatment than the previously-analyzed CH2-deleted form; Sck specifically interacts with a 135 kDa phosphoprotein (pp135) through its SH2 domain following membrane depolarization, and this interaction is reduced by Src kinase inhibitors.\",\n      \"method\": \"Genomic organization analysis; Western blot for EGF-induced phosphorylation; co-immunoprecipitation with SH2 domain; Src kinase inhibitor treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — domain-specific Co-IP with pharmacological inhibitor validation; single lab with multiple methods\",\n      \"pmids\": [\"11409899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ShcB (SHC2)-deficient mice exhibit a loss of peptidergic and nonpeptidergic nociceptive sensory neurons, demonstrating a unique role for ShcB in survival/maturation of nociceptive neurons; loss of both ShcB and ShcC causes significant loss of neurons in the superior cervical ganglia, indicating overlapping functions in sympathetic neuron development.\",\n      \"method\": \"Generation of ShcB and ShcC null mice; histological analysis of peripheral nervous system neurons in single and double knockout animals\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mice with defined cellular phenotypes, single/double KO comparison distinguishing unique and overlapping functions; single lab but multiple genetic conditions tested\",\n      \"pmids\": [\"11163269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ShcB (SHC2) and ShcC bind Trk receptors (TrkA at Y499, TrkB at Y515) via their N-terminal PTB domain in a phosphotyrosine-dependent manner, become tyrosine-phosphorylated in response to neurotrophin stimulation, and enhance MAPK activation in Trk-expressing cells; neurotrophin treatment of primary cortical neurons stimulates ShcB/ShcC–Trk interaction and ShcB/ShcC tyrosine phosphorylation in vivo.\",\n      \"method\": \"Co-immunoprecipitation in Trk-expressing cells and primary cortical neurons; phosphotyrosine-dependent binding assays; MAPK activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP in both heterologous cells and primary neurons, phosphotyrosine-dependence established, functional MAPK readout; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12006576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sck (SHC2) was identified as a downstream mediator indispensable for CD95-induced cell cycle progression in pancreatic ductal adenocarcinoma; CD95 drives tumour growth and metastasis via Sck.\",\n      \"method\": \"In silico RNA profile analysis; mechanistic follow-up in PDAC cancer stem cells and xenograft/syngeneic mouse models; pharmacological inhibition of CD95\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional placement of Sck downstream of CD95 in cancer cell lines and in vivo models, but mechanistic detail of Sck's biochemical role in cell cycle is limited in the abstract\",\n      \"pmids\": [\"25613377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ShcB (SHC2) knockout mice show defects in cerebellar-dependent motor function and impaired long-term depression (LTD) at cerebellar synapses, accompanied by impaired intracellular Ca2+ release from ER; the content of intracellular Ca2+ store and SERCA activity are decreased in ShcB-deficient cerebellum; ectopic re-expression of ShcB in KO Purkinje cells restores Ca2+ release and SERCA-dependent Ca2+ uptake.\",\n      \"method\": \"ShcB knockout mice; behavioral tests; cerebellar LTD electrophysiology; Ca2+ imaging; SERCA activity assay; rescue by ShcB re-expression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular and molecular phenotype, rescue experiment establishing causality, multiple orthogonal methods (electrophysiology, Ca2+ imaging, biochemical SERCA assay); single lab\",\n      \"pmids\": [\"32879382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ShcB (SHC2) acts downstream of TrkB in chondrocytes; silencing ShcB reverses the effects of TrkB overexpression on cell migration, angiogenesis, tube formation, and VEGF secretion in IL-1β-stimulated chondrocytes, placing ShcB as a required downstream effector in the TrkB/ShcB signaling axis.\",\n      \"method\": \"shRNA knockdown of ShcB and TrkB in chondrocytes; overexpression rescue; cell migration, invasion, proliferation, tube formation assays; VEGF ELISA; Western blot\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — epistasis by knockdown/overexpression in cell lines, multiple functional readouts, single lab\",\n      \"pmids\": [\"34107348\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SHC2 (ShcB/Sck) is a phosphotyrosine adapter protein expressed predominantly in neurons and endothelial cells that binds activated receptor tyrosine kinases (Trk receptors at specific phosphotyrosines via its PTB domain; KDR/VEGFR2 at Y1175 via its SH2 domain) to scaffold downstream signaling including MAPK activation; in neurons it is required for nociceptive and sympathetic neuron survival/development, and in cerebellar Purkinje cells it maintains ER Ca2+ store integrity by supporting SERCA activity, thereby enabling synaptic long-term depression; in cancer contexts it acts downstream of CD95 to promote cell cycle progression and metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SHC2 (ShcB/Sck) is a phosphotyrosine adapter protein that couples activated receptor tyrosine kinases to downstream MAPK signaling and governs neuronal survival and function [#6, #5]. It engages receptors through two distinct modular interfaces: its SH2 domain binds the VEGF receptor KDR/VEGFR2 at phosphotyrosine-1175 in a phosphorylation-dependent manner upon VEGF stimulation in endothelial cells, while its PTB domain binds Trk receptors (TrkA at Y499, TrkB at Y515) following neurotrophin stimulation [#1, #6]. Receptor engagement drives SHC2 tyrosine phosphorylation and enhances MAPK activation, and dominant-negative SH2 chimeras attenuate VEGF-induced MAPK signaling [#1, #6]. In the nervous system, SHC2 is required for survival and maturation of nociceptive sensory neurons and, redundantly with ShcC, for sympathetic neuron development [#5]. In cerebellar Purkinje cells it maintains ER Ca2+ store content and SERCA activity, an activity required for synaptic long-term depression and cerebellar motor function, as shown by knockout phenotypes rescued by ShcB re-expression [#8]. SHC2 also acts as a required downstream effector in disease contexts, mediating CD95-driven cell cycle progression and metastasis in pancreatic adenocarcinoma and TrkB-driven angiogenic responses in chondrocytes [#7, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that SHC2 is a receptor-specific adapter by defining its physical link to the VEGF receptor and mapping the interaction interface, answering how SHC2 connects to receptor tyrosine kinases.\",\n      \"evidence\": \"Yeast two-hybrid with KDR cytoplasmic domain, site-directed mutagenesis, and SH2/PTB deletion constructs\",\n      \"pmids\": [\"9790910\", \"10749680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish downstream signaling consequences\", \"Functional role in endothelial cells not yet tested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Distinguished SHC2 from the related neuronal adapter N-Shc, showing SHC2 has a unique binding partner (a 135 kDa phosphoprotein) and distinct kinase relationships, establishing functional non-redundancy among Shc family members.\",\n      \"evidence\": \"Immunoprecipitation in neuronal cells with NGF/BDNF stimulation and v-Src co-expression\",\n      \"pmids\": [\"9507002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the 135 kDa phosphoprotein unresolved\", \"Single-lab Co-IP without reciprocal validation\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Confirmed in physiological endothelial cells that the SHC2-KDR interaction occurs at Y1175 and contributes functionally to VEGF signaling, moving the interaction from yeast two-hybrid to native receptor signaling.\",\n      \"evidence\": \"Co-IP from VEGF-stimulated PAE cells, recombinant SH2-phosphopeptide binding, and dominant-negative chimera experiments\",\n      \"pmids\": [\"10749680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors recruited by SHC2 at KDR not identified\", \"MAPK attenuation shown only with artificial chimera\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the in vivo neuronal requirement for SHC2, answering whether the adapter is essential for development by revealing nociceptive neuron loss and redundancy with ShcC in sympathetic neurons.\",\n      \"evidence\": \"Single and double ShcB/ShcC knockout mice with histological analysis of peripheral neurons\",\n      \"pmids\": [\"11163269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor and signaling pathway driving the survival defect not yet linked\", \"Molecular mechanism of survival support unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Refined SHC2 biochemistry by showing the full-length p68 isoform is the efficiently phosphorylated form and that its SH2-mediated pp135 interaction is Src-dependent and depolarization-regulated.\",\n      \"evidence\": \"Genomic organization analysis, EGF-induced phosphorylation Western blots, SH2 Co-IP with Src inhibitor treatment\",\n      \"pmids\": [\"11409899\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"pp135 identity remains unknown\", \"Functional consequence of the depolarization-dependent interaction untested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected SHC2's neuronal role to a specific receptor class, showing PTB-domain binding to Trk receptors at defined phosphotyrosines drives neurotrophin-stimulated MAPK activation in primary neurons.\",\n      \"evidence\": \"Co-IP in Trk-expressing cells and primary cortical neurons, phosphotyrosine-dependent binding, and MAPK activation assays\",\n      \"pmids\": [\"12006576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between Trk binding and the in vivo neuronal survival phenotype not directly demonstrated\", \"Downstream effectors beyond MAPK not mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Solidified SHC2 expression in vascular endothelium and its VEGF-induced recruitment to KDR Y1175, integrating expression, localization, and signaling for the endothelial arm.\",\n      \"evidence\": \"RT-PCR, Western blot, immunohistochemistry, and Co-IP from VEGF-treated HUVEC and PAE cells\",\n      \"pmids\": [\"12214271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific endothelial functional output of SHC2 signaling not quantified\", \"Downstream adapters recruited by SHC2 unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended SHC2 into disease biology by placing it as an indispensable downstream mediator of CD95-driven cell cycle progression and metastasis in pancreatic cancer.\",\n      \"evidence\": \"In silico RNA profiling, PDAC cancer stem cell and xenograft/syngeneic models, and pharmacological CD95 inhibition\",\n      \"pmids\": [\"25613377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical mechanism linking SHC2 to cell cycle progression not defined\", \"Direct CD95-SHC2 physical interaction not shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed an unexpected non-canonical role for SHC2 in cerebellar Purkinje cells, where it maintains ER Ca2+ stores via SERCA activity to enable long-term depression, established causally by rescue.\",\n      \"evidence\": \"ShcB knockout mice with behavior, cerebellar LTD electrophysiology, Ca2+ imaging, SERCA assay, and re-expression rescue\",\n      \"pmids\": [\"32879382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between adapter function and SERCA regulation unknown\", \"Whether this role requires receptor tyrosine kinase input untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed SHC2 as a required downstream effector of TrkB in chondrocytes, showing it transmits TrkB-driven migration, angiogenesis, and VEGF secretion signals.\",\n      \"evidence\": \"shRNA knockdown and overexpression epistasis in IL-1\\u03b2-stimulated chondrocytes with functional and VEGF ELISA readouts\",\n      \"pmids\": [\"34107348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct TrkB-SHC2 interaction in chondrocytes not biochemically shown\", \"Single-lab cell-line epistasis without in vivo confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular identity of the SHC2-specific pp135 partner and the biochemical mechanism by which SHC2 controls SERCA activity and cell cycle progression remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"pp135 has not been identified\", \"No mechanistic link between SHC2 adapter function and SERCA/ER Ca2+ regulation\", \"No structural model of SHC2 receptor complexes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005068\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KDR\", \"NTRK1\", \"NTRK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}