Interactions between the discoidin domain receptor 1 and β1 integrin regulate attachment to collagen

Abstract

SummaryCollagen degradation by phagocytosis is essential for physiological collagen turnover and connective tissue homeostasis. The rate limiting step of phagocytosis is the binding of specific adhesion receptors, which include the integrins and discoidin domain receptors (DDR), to fibrillar collagen. While previous data suggest that these two receptors interact, the functional nature of these interactions is not defined. In mouse and human fibroblasts we examined the effects of DDR1 knockdown and over-expression on β1 integrin subunit function. DDR1 expression levels were positively associated with enhanced contraction of floating and attached collagen gels, increased collagen binding and increased collagen remodeling. In DDR1 over-expressing cells compared with control cells, there were increased numbers, area and length of focal adhesions immunostained for talin, paxillin, vinculin and activated β1 integrin. After treatment with the integrin-cleaving protease jararhagin, in comparison to controls, DDR1 over-expressing cells exhibited increased β1 integrin cleavage at the cell membrane, indicating that DDR1 over-expression affected the access and susceptibility of cell-surface β1 integrin to the protease. DDR1 over-expression was associated with increased glycosylation of the β1 integrin subunit, which when blocked by deoxymannojirimycin, reduced collagen binding. Collectively these data indicate that DDR1 regulates β1 integrin interactions with fibrillar collagen, which positively impacts the binding step of collagen phagocytosis and collagen remodeling.

The integrin–collagen connection – a glue for tissue repair?

“…DDRs have recently been shown to be able to activate collagen-binding integrins (Abbonante et al, 2013;Staudinger et al, 2013;Xu et al, 2012).…”

Directed differentiation of human iPSC into insulin producing cells is improved by induced expression of PDX1 and NKX6.1 factors in IPC progenitors

“…Conversion of renal epithelial cells into iPSC was the most effective on Geltrex matrix and recombinant Collagen I. Geltrex is a compound matrix comprising different proteins secreted by EHS sarcoma cells including laminins, entactin and collagens. Notably, Collagen type I and IV is thought to influence stem cells self-renewal, as their binding to integrin α2β1 and DDR1 receptor [36] activates Bmi-1 protein involved in cell proliferation [37]. …”

Mechanosensing via cell-matrix adhesions in 3D microenvironments

“…Over-expression of DDR1 stimulates β1 integrin binding to collagen, enhances 3D collagen reorganization, and increases 2D integrin activation and the formation of adhesions containing paxillin, talin, and vinculin, all of which could contribute to mechanosensing 76 . Genetic ablation of syndecan-4 reduces directional migration in 3D CDMs in a Rac1-dependent manner, and more recently syndecan-4 has been implicated in control of integrin recycling and 2D focal adhesion dynamics 77, 78 .…”