Trk receptor binding and neurotrophin/fibroblast growth factor (FGF)-dependent activation of the FGF receptor substrate (FRS)-3.
We have investigated the signaling properties of the fibroblast growth factor (FGF) receptor substrate 3 (FRS3), also known as SNT-2 or FRS2beta, in neurotrophin-dependent differentiation in comparison with the related adapter FRS2 (SNT1 or FRS2alpha). We demonstrate that FRS3 binds all neurotrophin Trk receptor tyrosine kinases and becomes tyrosine phosphorylated in response to NGF, BDNF, NT-3 and FGF stimulation in transfected cells and/or primary cortical neurons. Second, the signaling molecules Grb2 and Shp2 bind FRS3 at consensus sites that are highly conserved among FRS family members and that Shp2, in turn, becomes tyrosine phosphorylated. While FRS3 over-expression in PC12 cells neither increases NGF-induced neuritogenesis nor activation of Map kinase/AKT, comparable to previous reports on FRS2, over-expression of a chimeric adapter containing the PH/PTB domains of the insulin receptor substrate (IRS) 2, in place of the PTB domain of FRS3 (IRS2-FRS3) supports insulin-dependent Map kinase activation and neurite outgrowth in PC12 cells. Collectively, these data demonstrate that FRS3 supports ligand-induced Map kinase activation and that the chimeric IRS2-FRS3 adapter is stimulating sufficient levels of activated MapK to support neurite outgrowth in PC12 cells.
Dixon
Scott J
SJ
Laboratory of Neural Signaling, Cell Biology Group, The John P. Robarts Research Institute, London, Ontario, Canada N6A 5K8.
MacDonald
James I S
JI
Robinson
Kim N
KN
Kubu
Christopher J
CJ
Meakin
Susan O
SO
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D005346:Fibroblast Growth Factors / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000502:physiology*; D016716:PC12 Cells; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020917:Receptor, trkA / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D020812:Receptor, trkC / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D013379:Substrate Specificity / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; C113566:FRS3 protein, human; D009414:Nerve Growth Factors; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC