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  • Title: Differential utilization of ShcA tyrosine residues and functional domains in the transduction of epidermal growth factor-induced mitogen-activated protein kinase activation in 293T cells and nerve growth factor-induced neurite outgrowth in PC12 cells. Identification of a new Grb2.Sos1 binding site.
    Author: Thomas D, Bradshaw RA.
    Journal: J Biol Chem; 1997 Aug 29; 272(35):22293-9. PubMed ID: 9268379.
    Abstract:
    By transient expression of both truncated forms of p52(SHCA) and those with point mutations in 293T cells, it has been shown that, in addition to Tyr-317, Tyr-239/240 is a major site of phosphorylation that serves as a docking site for Grb2.Sos1 complexes. In addition, analysis of epidermal growth factor (EGF)-induced activation of mitogen-activated protein kinase in 293T cells showed that the overexpression Shc SH2 or phosphotyrosine binding (PTB) domains of ShcA alone has a more potent negative effect than the overexpression of the forms of ShcA lacking Tyr-317 or Tyr 239/240 or both. In transiently transfected PC12 cells, the ShcA PTB domain and tyrosine phosphorylation in the CH1 domain, especially on Tyr-239/240, are crucial for mediating nerve growth factor (NGF)-induced neurite outgrowth. These findings suggest that the EGF and NGF (TrkA) receptor can utilize Shc in different ways to promote their activity. For EGF-induced mitogen-activated protein kinase activation in 293T cells, both Shc PTB and SH2 domains are essential for optimal activation, indicating that a mechanism independent of Grb2 engagement with Shc may exist. For NGF-induced neurite outgrowth in PC12 cells, Shc PTB plays an essential role, and phosphorylation on Tyr-239/240, but not on Tyr-317, is required.
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