Our observation that FAK is downregulated
Our observation that FAK is downregulated in vascular smooth muscle VER155008 on fibrillar collagen confirms observations reported for other cell types . However, unlike the results reported previously , our work suggests that matrix rigidity per se does not determine FAK downregulation. This conclusion is based both on the fact that we observe FAK downregulation in cells on matrices of different stiffness (comparing untreated and dehydrated collagen fibrils), and either FAK downregulation or lack of FAK downregulation in cells on matrices of similar stiffness (comparing dehydrated and deglycosylated collagen fibrils). A correlation between cell spreading and MLC phosphorylation was observed regardless of whether or not FAK was downregulated, further supporting the notion that cell response to matrix stiffness does not determine FAK levels. Previous studies have shown that complete loss of FAK can influence MLC phosphorylation , . In this study, we do not see a correlation between FAK downregulation and MLC phosphorylation or cell spreading. However, in these experiments FAK is only partially depleted, and it is possible thhis incomplete depletion of FAK is why we observe no effect on MLC phosphorylation.
Introduction Collagen deposition is a common feature found in cancerous tissues and fibrotic organs/lesions. It is now well accepted that collagen deposition is not just a consequence of disease, but that it can also trigger a vicious cycle. Both chemical and physical signals elicited from collagen are involved in fibrotic disease progression (for concise reviews of this field: [, , ]). Therefore, how cells transmit collagen signals and how these signals are regulated are critical issues in unveiling the underlying mechanism of disease progression. Integrins and discoidin domain receptors (DDRs) are the two most important and ubiquitously expressed collagen receptors. Four integrin heterodimers, including α1β1, α2β1, α10β1, and α11β1, show different binding affinities to different types of collagen, tissue-specific expression patterns, and different effects in development and disease progression [4,5]. Many emerging roles of DDRs in cell differentiation, development and disease progression have been discovered in this decade, and there are still many intriguing issues to be explored. Glycoprotein VI is another type of collagen receptor found in platelets, and it plays a critical role in collagen-induced platelet activation and aggregation [6,7]. This review focuses on the roles of DDRs.
Roles of DDR1 in epithelial cell differentiation
Roles of DDR1 in cell migration, and invasion
Dichotomous functions of DDR1 in disease progression
Conclusions and perspectives The switch in expression from DDR1 to DDR2 during EMT is another important issue. The DDRs may exert distinct or redundant functions. Further studies of the diverse signaling pathways mediated by the DDRs might provide new insight into the distinct functions of the DDRs. DDR1 down-regulation is not always observed during EMT, especially in cancerous tissues (Fig. 3). In fact, increased DDR1 expression is found in many malignant tumors. The dichotomous functions and dual faces of DDR1 lead to the issue of whether DDR1 is actually a suitable therapeutic target for cancer therapy. Another remaining issue is what causes the loss of sensitivity to the EMT-inducer that triggers DDR1 downregulation and in what types of cancer is this process relevant. Excessive collagen deposition and remodeling are regularly seen in fibrotic lesions and cancerous tissue. Increased collagen signaling not only impairs tissue architecture but also impacts tissues homeostasis, which can impair organ functions or accelerate cancer cell malignancy. Therefore, modulation of collagen signaling becomes a critical issue. The development of DDR inhibitors has shed some light on possible treatments for many diseases [107,, , , , , ]. However, many of these drugs can inhibit the kinase activities of both DDRs but not their kinase-independent functions. Drug discovery is still an important issue, and further assessment of the power of DDRs as therapeutic targets is need.