(607d) Cadherin 11 Modulate Fibroblast Growth Via Cooperation with Platelet Derived Growth Factor Receptor Beta
Materials and Methods: Mouse tissues were isolated from Cdh11-/- (Cdh11-/- knockout, KO) and WT-wild type mice for cell isolation and immunostaining. Lentivirus encoded shRNA was used to knock down CDH11 in vitro. An engineered surface with and immobilized fusion protein containing the extracellular CDH11 domain fused to the Fc domain (CDH11-Fc) was employed as a tool to study immediate downstream effects and identify the mechanism of intracellular signaling following CDH11 engagement. Co-immunoprecipitation was used to test the partners of CDH11.
Results and Discussion: We discovered that CDH11 plays a critical role in mediating fibroblast cell growth. Specifically, engagement of CDH11 promotes fibroblast proliferation, while CDH11 deficiency decrease the proliferation rate significantly. In agreement, the dermis of Cdh11-/- was much thinner and contained fewer cells as compared to wild type animals. Interestingly, CDH11 engagement upregulated the expression of platelet derived growth factor receptor beta (PDGFRÎ²), as evidenced by shCDH11 knockdown in human fibroblasts and cdh11-/- mouse cells. Most notably, CDH11 was found to form a complex with PDGFRÎ² and synergistically enhanced PDGFRÎ² - AKT signaling cascade. This association with CDH11 led to elevation of the sensitivity of PDGFRÎ² to its ligands by 10- to 100-fold, ultimately promoting cell proliferation even under conditions of nutrient deprivation.
Conclusions: Taken together, our results demonstrate a novel role of CDH11 in regulating fibroblast growth through synergistic interaction with PDGFRÎ² and suggest a novel mechanism that involves the physical interaction of CDH11 with a growth factor receptor and modulates its sensitivity to the ligands. Our results provide better understanding of cell survival and proliferation even under nutrient deprivation, which may have significant implications in epithelial-to-mesenchymal transition and tumor metastasis.
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