Abstract

How multiple receptor tyrosine kinases coordinate cell fate determination is yet to be elucidated. We show here that the receptor for platelet-derived growth factor (PDGF) signaling recruits the p85 subunit of Phosphoinositide 3-kinase (PI3K) to regulate mammalian lens development. Activation of PI3K signaling not only prevents B-cell lymphoma 2 (BCL2)-Associated X (Bax)- and BCL2 Antagonist/Killer (Bak)-mediated apoptosis but also promotes Notch signaling to prevent premature cell differentiation. Reducing PI3K activity destabilizes the Notch intracellular domain, while the constitutive activation of Notch reverses the PI3K deficiency phenotype. In contrast, fibroblast growth factor receptors (FGFRs) recruit Fibroblast Growth Factor Receptor Substrate 2 (Frs2) and Rous sarcoma oncogene (Src) Homology Phosphatase 2 (Shp2) to activate Mitogen-Activated Protein Kinase (MAPK) signaling, which induces the Notch ligand Jagged 1 (Jag1) and promotes cell differentiation. Inactivation of Shp2 restored the proper timing of differentiation in the p85 mutant lens, demonstrating the antagonistic interaction between FGF-induced MAPK and PDGF-induced PI3K signaling. By selective activation of PI3K and MAPK, PDGF and FGF cooperate with and oppose each other to balance progenitor cell maintenance and differentiation.

Highlights

  • Receptor Tyrosine Kinases (RTKs) are a large family of membrane proteins that can activate a common set of downstream pathways, but they are known to elicit distinct biological responses

  • We showed that platelet-derived growth factor (PDGF) signaling primarily activates the Phosphoinositide 3-kinase (PI3K)–Protein kinase B (AKT) pathway in lens development and the direct binding of PI3K to platelet-derived growth factor receptor α (PDGFRα) is required for preventing the depletion of lens epithelial cells

  • At mouse embryonic day 14.5 (E14.5), Pdgfrα is exclusively expressed in the lens epithelium, as indicated by RNA in situ hybridization and a green fluorescent protein (GFP) reporter from the Pdgfrα locus (Fig 1B, arrowheads)

Read more

Summary

Introduction

Receptor Tyrosine Kinases (RTKs) are a large family of membrane proteins that can activate a common set of downstream pathways, but they are known to elicit distinct biological responses. In lens explant cultures, FGFs have been shown to promote either epithelial cell proliferation or fiber-cell differentiation in a dose-dependent manner [4]. This is supported by in vivo evidence that transgenic expressions of FGFs cause premature differentiation of lens epithelial cells into fiber cells, while deletion of FGFRs or their coreceptor heparan sulfates abrogate lens fiber differentiation [5,6,7,8]

Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call