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

Abstract

Erk1/Erk2 MAP kinases are key regulators of cell behaviour and their activation is generally associated with tyrosine kinase signalling. However, TGF-beta 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-beta stimulation, the activated TGF-beta type I receptor (TbetaRI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic TbetaRI tyrosine kinase activity that complements its well-defined serine-threonine kinase function. TGF-beta-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 TbetaRI is tyrosine phosphorylated in response to TGF-beta. Thus, TbetaRI, like the TGF-beta type II receptor, is a dual-specificity kinase. Recruitment of tyrosine kinase signalling pathways may account for aspects of TGF-beta biology that are independent of Smad signalling.

Mutant p53 Disrupts Role of ShcA Protein in Balancing Smad Protein-dependent and -independent Signaling Activity of Transforming Growth Factor-β (TGF-β)

“…TGF-␤ receptors have been shown to possess dual tyrosine and serine kinase activity and can directly tyrosine phosphorylate ShcA to activate Ras/MAPK signaling or serine phosphorylate ShcA with an unclear consequence (10). The same study suggests that tyrosine phosphorylation of p66Shc, the inhibitory isoform of ShcA, is more dependent on RI in untransformed cells.…”

“…The integration of TGF-␤-mediatedSmad-dependent and -independent signaling is believed to contribute to the key events of TGF-␤-induced tumor progression including ERK signaling-mediated cell migration (8,9). TGF-␤ activates Ras/ERK signaling through the direct phosphorylation of the adaptor protein ShcA (10). ShcA belongs to the family of Shc adaptor proteins, which are substrates of receptor tyrosine kinases (11).…”

Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans

“…Thus, notwithstanding the involvement of TGF-β1 in CAVD, blocking those pathways may not be an option for treating CAVD and atherosclerosis. However, recent evidence has shown that TGF-β1 signalling pathways are much more complex and can involve tyrosine and serine/threonine phosphorylation and activation of MAP kinases , particularly ERK and p38 [56][57][58]. This investigation demonstrated a small but not statistically significant level of MAP kinase activity in VICs associated with TGFβ1-mediated Smad phosphorylation however this may reflect the 4 hour time point studied.…”

High glucose activates PKC-ζ and NADPH oxidase through autocrine TGF-β1 signaling in mesangial cells

“…Several mechanisms have been proposed for non-Smad TGF-␤ 1 signaling. For instance, T␤RI activates ERK by directly phosphorylating ShcA (27). PI3 kinase associates indirectly with T␤RI (66), and TGF-␤ 1 -induced Akt phosphorylation occurs independently of Smads in fibroblasts (60).…”