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  • 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.

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.

The Journal of biological chemistry (2013-01-02)
Jason J Northey, Zhifeng Dong, Elaine Ngan, Andrew Kaplan, W Rod Hardy, Tony Pawson, Peter M Siegel
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal Anti-α-Tubulin antibody produced in mouse, clone DM1A, ascites fluid
Sigma-Aldrich
Anti-c-ErbB2/c-Neu (Ab-4) Mouse mAb (7.16.4), liquid, clone 7.16.4, Calbiochem®
Sigma-Aldrich
Monoclonal ANTI-FLAG® M2 antibody produced in mouse, 1 mg/mL, clone M2, affinity isolated antibody, buffered aqueous solution (50% glycerol, 10 mM sodium phosphate, and 150 mM NaCl, pH 7.4)
Sigma-Aldrich
O-Phospho-L-tyrosine