Journal
EMBO JOURNAL
Volume 26, Issue 17, Pages 3957-3967Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.emboj.7601818
Keywords
Erk; MAP kinase; receptor; ShcA/TGF-beta
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Funding
- NCI NIH HHS [R01 CA63101, R01 CA063101] Funding Source: Medline
- NHLBI NIH HHS [R01 HL62317, P01 HL60231, P01 HL060231, R01 HL062317] Funding Source: Medline
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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-b stimulation, the activated TGF-beta type I receptor (T beta RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic TbRI 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 TbRI is tyrosine phosphorylated in response to TGF-beta. Thus, TbRI, 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.
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