Protein Prospecting

FGF induces specific effects when compared with other growth factors. This specificity will emanate from the involvement of unique proteins and protein combinations in FGF signal transduction. The identification and characterization of novel proteins involved in FGF signaling is the laboratory’s aim.

The areas in the FGF signal transduction pathway that the lab are ‘prospecting’ for novel proteins. FRS2 (inset) was recently discovered in area "1" using protocols outlined below.

Five years ago when the Guy laboratory decided to investigate the signal transduction of Fibroblast Growth Factor (FGF) little was known about the proteins involved in the early stages of the pathway that lead to the physiological effects induced by the factor. The receptors were known to dimerize and autophosphorylate on several defined sites, resulting in the activation of the Ras/Map kinase pathway via Grb2 and Sos. The lab set out to identify and characterize proteins that were present at stage 1 (proteins that interacted directly with the receptor) or stage 2 (proteins that modified the Ras/Map kinase pathway).

Strategy Dr. Guy’s group has employed three basic approaches to achieve their objectives. They are:

(a) To assume that early signaling pathways, especially those connecting receptors to the Ras/Map kinase pathway, involve the mediation of the adaptor protein Grb2 Lab members have gone ‘fishing’ with the SH3 and SH2 domains of Grb2 to ‘hook’ novel interacting proteins. This approach, by them and others, led to the discovery and characterization of FRS2 (a stage 1 protein in figure inset).

(b) Using a two-hybrid strategy other members of the lab have used the cytosolic part of the FGF receptor to locate novel proteins involved in the FGF signaling pathway.

(c) A more recent strategy is to investigate the human homologues of Drosophila or C. elegans that have been genetically shown to be involved in the FGF pathways of those two organisms. These systems have proven invaluable in the past to identify important mammalian homologues to various vital pathway components such as Grb2, Sos, SHP2 and SHP1.

Medical Implications FGF signaling has been shown to be very important in embryonic development and signaling in mature mammals. Drugs targeting various parts of the FGF receptors are in advanced stages of clinical trials as possible inhibitors of FGF-mediated angiogenesis necessary to support and sustain certain tumor mass. A closer understanding of components and interactions within the pathway may enable better drugs to be developed.