VEGF signaling is central to a number of processes including angiogenesis and arteriogenesis, regulation of vascular permeability and blood pressure and various inflammatory responses among many others. VEGFs exert their effects by binding to three related receptor tyrosine kinases (RTKs)- VEGFR1, R2 and R3. Studies from ours and other laboratories have shown that VEGFR2 activation of ERK cascade that is critical both in early vascular development and adult arteriogenesis, requires VEGFR2 endocytosis and trafficking. Yet this link between endocytosis and signaling is still poorly understood with very little known about the players involved. Our preliminary data indicates that FRS2a, the key mediator of FGFR signaling, plays a critical role in VEGFR2-dependent activation of ERK and VEGR2 endocytosis. FRS2a involvement in VEGF signaling is highly unexpected because VEGFR2 lacks known FRS2a binding sites. However, if correct, this would be very important, for a number of reasons: 1. This identifies a new protein directly regulating VEGFR2 signaling and endocytosis. 2. It establishes a new link between FGF and VEGF signaling. 3. VEGFR2 does not have any canonical FRS2a PTB binding sites. Identification of a new binding site would expand our understanding of PTB- mediated cellular protein network formation. 4. FRS2a role goes well beyond VEGFR2 as it also binds VEGFR1 and R3. Thus, FRS2a may be quite central to all of VEGF signaling and to vascular biology. While this grant will focus on VEGFR2, we will explore, in parallel, FRS2a interactions with other VEGFRs as appropriate. Finally, the unexpected role of FRS2a in VEGFR signaling has profound biological implications since the fact that a single molecule affects both VEGF and FGF signaling is critically important not only for our understanding of VEGF biology per se but also for understanding of VEGF/FGF (or, potentially other RTK) cross-talk and the development of drugs designed to selectively affect VEGF signaling. The latter, in turn, is crucial to development of therapeutic interventions aimed at both stimulation and inhibition of blood vessel growth.
We have identified that a docking protein, FRS2a, plays a central role in regulation of VEGF signaling. This unexpectedly links VEGF and FGF signaling pathways and sheds new light on the most fundamental aspects of vascular biology. Furthermore, this discovery provides new opportunities for drug development for patients with cancer and cardiovascular diseases.
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