TGF-β activates Erk MAP kinase signalling through direct phosphorylation of ShcA

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Abstract
Erk1/Erk2 MAP kinases are key regulators of cell behaviour and their activation is generally associated with tyrosine kinase signalling. However, TGF‐β stimulation also activates Erk MAP kinases through an undefined mechanism, albeit to a much lower level than receptor tyrosine kinase stimulation. We report that upon TGF‐β stimulation, the activated TGF‐β type I receptor (TβRI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic TβRI tyrosine kinase activity that complements its well‐defined serine‐threonine kinase function. TGF‐β‐induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well‐characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. We also found that TβRI is tyrosine phosphorylated in response to TGF‐β. Thus, TβRI, like the TGF‐β type II receptor, is a dual‐specificity kinase. Recruitment of tyrosine kinase signalling pathways may account for aspects of TGF‐β biology that are independent of Smad signalling.