Aberrant FGF receptor (FGFR) signaling drives the malignancy of a number of human cancers and also is responsible for a number of human developmental disorders. Likewise, PTEN is a well-known tumor suppressor gene that is inactivated in a large variety of human tumors. FGFRs are receptor tyrosine kinases (RTKs) that activate many cellular responses through a signal transduction pathway that activates both AKT and ERK signaling. Despite their central importance to human health, detailed mechanistic understanding of how Fgfr stimulation dictates diverse cellular responses in different tissues remains incomplete. PTEN is a phosphatase that exhibits activity both on lipids and proteins. Recent literature suggests that FGFR signaling and PTEN signaling genetically interact. The ocular lens is a relatively simple developmental system in which FGFR signaling plays an important role. Inhibition of FGFR activity in vivo leads to lens cell apoptosis and overexpression or exogenous administration of FGF leads to fiber cell differentiation in lens epithelial cells. To dissect the role of FGFR signaling in lens cell survival and differentiation, this application proposes to genetically remove FGFR signaling in the lens both in vivo and in lens explants to decouple survival signals from differentiation signals This proposal will test the hypothesis that PTEN inhibits FGFR- mediated survival without inhibiting FGFR-mediated fiber cell differentiation. In addition to revealing the underlying mechanism by which PTEN regulates FGFR signaling the aims of the proposal will develop the first comparative transcriptome of lens cells with intact and deficient FGFR signaling in differentiating conditions with and without regulation by PTEN.
Aberrant FGFR signaling lies at the heart of many developmental abnormalities as well as many different cancers. Likewise PTEN is a tumor suppressor whose heterozygous mutation predisposes to many cancers and developmental growth syndromes. Recently several studies have demonstrated a strong interaction between these pathways. The lens is a relatively simple developmental system where FGFR signaling clearly plays an important role. The studies proposed in this application will elucidate the mechanisms by which these signaling pathways interact to achieve cell survival and differentiation, which are key pathways disrupted in oncogenesis. A better understanding of how these signaling pathways interact in vivo will permit rational design of pharmaceutical to target these pathways when they go awry.
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