title: Distinct phosphotyrosine-dependent functions of the ShcA adaptor protein are required for transforming growth factor β (TGFβ)-induced breast cancer cell migration, invasion, and metastasis.
abstract: The ErbB2 and TGFβ signaling pathways cooperate to promote the migratory, invasive, and metastatic behavior of breast cancer cells. We previously demonstrated that ShcA is necessary for these synergistic interactions. Through a structure/function approach, we now show that the phosphotyrosine-binding, but not the Src homology 2, domain of ShcA is required for TGFβ-induced migration and invasion of ErbB2-expressing breast cancer cells. We further demonstrate that the tyrosine phosphorylation sites within ShcA (Tyr(239)/Tyr(240) and Tyr(313)) transduce distinct and non-redundant signals that promote these TGFβ-mediated effects. We demonstrate that Grb2 is required specifically downstream of Tyr(313), whereas the Tyr(239)/Tyr(240) phosphorylation sites require the Crk adaptor proteins to augment TGFβ-induced migration and invasion. Furthermore, ShcA Tyr(313) phosphorylation enhances tumor cell survival, and ShcA Tyr(239)/Tyr(240) signaling promotes endothelial cell recruitment into ErbB2-expressing breast tumors in vivo, whereas all three ShcA tyrosine residues are required for efficient breast cancer metastasis to the lungs. Our data uncover a novel ShcA-dependent signaling axis downstream of TGFβ and ErbB2 that requires both the Grb2 and Crk adaptor proteins to increase the migratory and invasive properties of breast cancer cells. In addition, signaling downstream of specific ShcA tyrosine residues facilitates the survival, vascularization, and metastatic spread of breast tumors.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Northey
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Dong
authors.forename: Elaine
authors.initials: E
authors.lastname: Ngan
authors.forename: Andrew
authors.initials: A
authors.lastname: Kaplan
authors.forename: W Rod
authors.initials: WR
authors.lastname: Hardy
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siegel
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D002465:Cell Movement; D002470:Cell Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D019000:Phosphotyrosine; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D053773:Transforming Growth Factor beta1; C528024:SHC1 protein, human; C508053:ERBB2 protein, human