TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA.
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.
Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA. mattlee@usc.edu
Matt K
MK
Lee
Cécile
C
Pardoux
Marie C
MC
Hall
Pierre S
PS
Lee
David
D
Warburton
Jing
J
Qing
Susan M
SM
Smith
Rik
R
Derynck
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D020839:Son of Sevenless Protein, Drosophila / Q000378:metabolism; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D016212:Transforming Growth Factor beta / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D018125:Receptors, Transforming Growth Factor beta; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D020839:Son of Sevenless Protein, Drosophila; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D016212:Transforming Growth Factor beta; D048049:Extracellular Signal-Regulated MAP Kinases