The Shb Adaptor Protein Binds to Tyrosine 766 in the FGFR-1 and Regulatesthe Ras/MEK/MAPK Pathway via FRS2 Phosphorylation in Endothelial Cells

Cross, Michael JUppsala universitet,Institutionen för genetik och patologi (författare)

Stimulation of fibroblast growth factor receptor-1 (FGFR-1) is known to result in phosphorylation of tyrosine 766 and the recruitment and subsequent activation of phospholipase C-γ (PLC-γ). To assess the role of tyrosine 766 in endothelial cell function, we generated endothelial cells expressing a chimeric receptor, composed of the extracellular domain of the PDGF receptor-α and the intracellular domain of FGFR-1. Mutation of tyrosine 766 to phenylalanine prevented PLC-γ activation and resulted in a reduced phosphorylation of FRS2 and reduced activation of the Ras/MEK/MAPK pathway relative to the wild-type chimeric receptor. However, FGFR-1–mediated MAPK activation was not dependent on PKC activation or intracellular calcium, both downstream mediators of PLC-γ activation. We report that the adaptor protein Shb is also able to bind tyrosine 766 in the FGFR-1, via its SH2 domain, resulting in its subsequent phosphorylation. Overexpression of an SH2 domain mutant Shb caused a dramatic reduction in FGFR-1–mediated FRS2 phosphorylation with concomitant perturbment of the Ras/MEK/MAPK pathway. Expression of the chimeric receptor mutant and the Shb SH2 domain mutant resulted in a similar reduction in FGFR-1–mediated mitogenicity. We conclude, that Shb binds to tyrosine 766 in the FGFR-1 and regulates FGF-mediated mitogenicity via FRS2 phosphorylation and the subsequent activation of the Ras/MEK/MAPK pathway.

Lu, LinggeUppsala universitet,Institutionen för medicinsk cellbiologi (författare)
Magnusson, PeetraUppsala universitet,Institutionen för genetik och patologi(Swepub:uu)petrmagn (författare)
Nyqvist, DanielUppsala universitet,Institutionen för genetik och patologi (författare)
Holmqvist, KristinaUppsala universitet,Institutionen för medicinsk cellbiologi (författare)
Welsh, MichaelUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)michwels (författare)
Claesson-Welsh, LenaUppsala universitet,Institutionen för genetik och patologi(Swepub:uu)lcl04207 (författare)
Uppsala universitetInstitutionen för genetik och patologi (creator_code:org_t)

Av författaren/redakt...: Cross, Michael J; Lu, Lingge; Magnusson, Peetr ...; Nyqvist, Daniel; Holmqvist, Krist ...; Welsh, Michael; visa fler...; Claesson-Welsh, ...; visa färre...

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