(607d) Cadherin 11 Modulate Fibroblast Growth Via Cooperation with Platelet Derived Growth Factor Receptor Beta

Introduction: Cadherin 11 (CDH11) as a typical type II cadherin plays an essential role in ranging from cellular adhesion to maintenance of tissue integrity and homeostasis. Recent studies in our lab also revealed that engagement of cadherin 11 through homotypic binding is necessary for the differentiation process of mesenchymal stem cell (MSC) to smooth muscle cell (SMC)¹. Deficiency of CDH11, not only compromises the MSC differential potential but also leads to reduced collagen and elastin synthesis, resulting in reduced mechanical property of tissues such as skin, bladder and aorta². Here we report our recent discovery, that in cooperation with platelet derived growth factor receptor (PDGFRβ), CDH11 regulate cell growth via the PDGFRβ-AKT axis. Through interaction with CDH11, the sensitivity of PDGFR to its ligands is enhanced by 10-100 times, thereby promoting cell proliferation

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 (PDGFRβ), as evidenced by shCDH11 knockdown in human fibroblasts and cdh11^-/- mouse cells. Most notably, CDH11 was found to form a complex with PDGFRβ and synergistically enhanced PDGFRβ - AKT signaling cascade. This association with CDH11 led to elevation of the sensitivity of PDGFRβ 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 PDGFRβ 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.

1. Alimperti, S., You, H., George, T., Agarwal, S.K. & Andreadis, S.T. Cadherin-11 regulates both mesenchymal stem cell differentiation into smooth muscle cells and the development of contractile function in vivo. J Cell Sci 127, 2627-2638 (2014).
2. Row, S., Liu, Y., Alimperti, S., Agarwal, S.K. & Andreadis, S.T. Cadherin-11 is a novel regulator of extracellular matrix synthesis and tissue mechanics. J Cell Sci 129, 2950-2961 (2016).