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.
Highlights
ShcA integrates TGF and ErbB2 signaling in breast cancer
Through a structure/function approach, we show that the phosphotyrosine-binding, but not the Src homology 2, domain of ShcA is required for TGFinduced migration and invasion of ErbB2-expressing breast cancer cells
Simultaneous Reduction of Grb2 and Crk Adaptor Proteins in ErbB2-expressing Cells Renders Them Refractory to TGF-induced Migration and Invasion—We examined whether Grb2 and Crk are the primary signaling complexes recruited to ShcA to increase TGF-induced breast cancer cell invasion
Summary
ShcA integrates TGF and ErbB2 signaling in breast cancer. Results: Distinct motifs within ShcA facilitate TGF-induced effects in ErbB2-expressing cells. We previously identified the ShcA adaptor protein as an important mediator of the synergistic migratory and invasive effects observed downstream of the TGF and ErbB2 signaling pathways [3]. We demonstrate that the ShcA adaptor requires the PTB, and not the SH2, domain for TGF-induced migration and invasion of ErbB2-expressing breast cancer cells. The Tyr239/Tyr240 and Tyr313 phosphorylation sites transduce critical and non-redundant signals through the Crk and Grb adaptor proteins, respectively, to augment TGF-induced breast cancer cell migration and invasion. Signals emanating from these distinct ShcA tyrosine residues promote the vascularization (Tyr239/Tyr240) and survival (Tyr313) of tumor cells in vivo. All three tyrosine residues are required for efficient dissemination of breast cancer cells to the lungs
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