Interaction of Proteoglycans with Receptor Tyrosine Kinases

Abstract

The control of cell proliferation depends on the interactions between growth factors and their specific receptor-activated signaling pathways. It is well accepted that the local extracellular matrix can modulate cellular responses to a given signal in several ways, such as by modulating the affinity of the ligand for its cognate receptor (1), by binding and limiting availability of a growth factor (1–3), or by influencing proteolytic processing and internalization (3). However, it has only recently been shown that “structural” components of the extracellular matrix can interact directly with, and activate, receptor tyrosine kinases (RTKs). This was first shown by Vogel et al. and Shrivastava et al., who demonstrated that the “orphan” receptor tyrosine kinases DDR1 and DDR2 in fact bind fibrillar collagen (4,5). This binding required the native triplehelical structure of collagen and showed much slower kinetics than observed with other ligand-receptor interactions (5). Decorin (6–8), a member of a family of small leucine-rich proteoglycans (3), binds to fibrillar collagen and is an important regulator of matrix assembly (9–11). Decorin content is elevated in the tumor stroma of colon cancer (11), and ectopic expression of decorin inhibits cell growth (11–13). The growth-suppressive properties of decorin are independent of p53 or retinoblastoma proteins but require functional p21 protein (Waf1/Cip1/Sdi1) (13–16).