Frs2 enhances fibroblast growth factor-mediated survival and differentiation in lens development.
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Most growth factor receptor tyrosine kinases (RTKs) signal through similar intracellular pathways, but they often have divergent biological effects. Therefore, elucidating the mechanism of channeling the intracellular effect of RTK stimulation to facilitate specific biological responses represents a fundamental biological challenge. Lens epithelial cells express numerous RTKs with the ability to initiate the phosphorylation (activation) of Erk1/2 and PI3-K/Akt signaling. However, only Fgfr stimulation leads to lens fiber cell differentiation in the developing mammalian embryo. Additionally, within the lens, only Fgfrs activate the signal transduction molecule Frs2. Loss of Frs2 in the lens significantly increases apoptosis and decreases phosphorylation of both Erk1/2 and Akt. Also, Frs2 deficiency decreases the expression of several proteins characteristic of lens fiber cell differentiation, including Prox1, p57(KIP2), aquaporin 0 and -crystallins. Although not normally expressed in the lens, the RTK TrkC phosphorylates Frs2 in response to binding the ligand NT3. Transgenic lens epithelial cells expressing both TrkC and NT3 exhibit several features characteristic of lens fiber cells. These include elongation, increased Erk1/2 and Akt phosphorylation, and the expression of -crystallins. All these characteristics of NT3-TrkC transgenic lens epithelial cells depend on Frs2. Therefore, tyrosine phosphorylation of Frs2 mediates Fgfr-dependent lens cell survival and provides a mechanistic basis for the unique fiber-differentiating capacity of Fgfs on mammalian lens epithelial cells.
author list (cited authors)
Madakashira, B. P., Kobrinski, D. A., Hancher, A. D., Arneman, E. C., Wagner, B. D., Wang, F., ... Robinson, M. L.
complete list of authors
Madakashira, Bhavani P||Kobrinski, Daniel A||Hancher, Andrew D||Arneman, Elizabeth C||Wagner, Brad D||Wang, Fen||Shin, Hailey||Lovicu, Frank J||Reneker, Lixing W||Robinson, Michael L