Epithelial–mesenchymal transition (EMT) is induced by transforming growth factor-β (TGFβ), but can be further augmented by epidermal growth factor (EGF). EGF initiates its own signalling network, including through extracellular-signal-regulated kinases (ERKs), the activation of which relies on the proto-oncogene SH2 domain-containing phosphatase-2 (SHP2). However, how SHP2 affects the ability of EGF to augment EMT remains unknown. In this issue (p. ), Matthew Lazzara and colleagues use lung and pancreatic cancer cells to demonstrate how the structure and function of SHP2 correlate with its role in EMT signalling. They confirm that TGFβ-induced EMT, as measured by reduced levels of E-cadherin, as well as increased vimentin expression and cell migration, is enhanced by EGF treatment. The importance of SHP2 in EMT is underscored by the authors’ observations that SHP2 knockdown (KD) promotes epithelial phenotypes, hampers ERK activation and inhibits EMT induced by TGFβ, EGF or the combination of both. They further demonstrate that EGF, but not TGFβ, promotes SHP2 binding of tyrosine-phosphorylated GAB1. Moreover, a SHP2 mutant unable to bind phosphotyrosine does not associate with GAB1, activate ERK or rescue EMT inhibition observed in SHP2 KD cells. These findings indicate that SHP2 binding of phosphotyrosine on GAB1 underlies EGF augmentation of TGFβ-induced EMT, as it is needed for efficient downstream activation of ERK signalling. Given that EMT is linked to metastasis, identification of SHP2 as a key signalling effector might be of tremendous importance for developing novel anti-cancer therapies.
