br Materials and Methods br Acknowledgements br Introduction
Materials and Methods
Introduction The discoidin domain receptors, DDR1 and DDR2, are two closely related receptor tyrosine kinases (RTKs) that contain a discoidin (DS) homology domain in their extracellular regions. The DDRs were initially discovered by homology cloning based on their catalytic kinase domains and were orphan receptors until 1997, when two independent groups discovered that several different types of collagen are functional DDR ligands (Shrivastava et al., 1997, Vogel et al., 1997). RTKs are a large family (58 proteins in humans) of single-pass transmembrane receptors, characterized by structurally diverse extracellular ligand-binding regions and conserved cytosolic kinase domains. Based on their extracellular domain architecture, RTKs are divided into 20 subfamilies. RTK-dependent cellular signaling controls critical cellular processes, such as proliferation and differentiation, cell survival, cell migration, and Tarafenacin control (Lemmon and Schlessinger, 2010). Typical RTKs (exemplified by the most studied receptors, members of the EGF, and insulin receptor subfamilies) are activated by soluble peptide-like growth factors. It was therefore surprising that the DDRs are activated by collagens, major components of all types of extracellular matrix (ECM) (Kadler et al., 2007). Before this discovery, integrins were considered to be the only class of cell surface receptors that could transmit signals into cells by binding ECM components. Integrins are heterodimers of noncovalently associated α and β chains that constitute the main family of ECM receptors for cell adhesion (Hynes, 2002). Of the 24 distinct integrins in higher vertebrates, four serve as collagen-binding receptors (Leitinger, 2011). The DDRs have a longer evolutionary history than the collagen-binding integrins: DDR homologues are found in invertebrates, such as worms, insects, and hydra, while collagen-binding integrins are restricted to vertebrates (Leitinger, 2011). A recent study defined a role for Caenorhabditis elegans DDRs as receptors that guide axons along major longitudinal tracts (Unsoeld et al., 2013). Like vertebrates, C. elegans has two ddr genes, but it is not clear whether the DDRs function as collagen receptors in C. elegans. Because the DDRs did not genetically interact with CLE-1, the only known collagen involved in axon guidance, it was concluded that CLE-1 is not a DDR ligand in this process (Unsoeld et al., 2013). However, it remains to be seen whether other C. elegans collagens interact with the DDRs in axon guidance. RTKs transmit signals into cells by providing docking sites for effector molecules in the form of phosphorylated cytoplasmic tyrosines, a result of ligand-induced kinase activation and receptor autophosphorylation (Lemmon and Schlessinger, 2010). Upon collagen binding, the DDRs undergo autophosphorylation with very slow and sustained kinetics (Shrivastava et al., 1997, Vogel et al., 1997), a unique feature that distinguishes them from other RTKs. While we understand the molecular basis of the DDR–collagen interaction at the level of the isolated ligand-binding region, the biochemical and cellular mechanisms that control receptor activation on the surface of cells remain undefined. Like other RTKs, the DDRs regulate key cellular processes including cell migration, cell proliferation, cell differentiation, and cell survival. Additionally, the DDRs control remodeling of ECMs through the control of matrix metalloproteinase (MMP) expression and activity and have overlapping functions with collagen-binding integrins. This review provides an overview of the current knowledge of DDR structure and their tissue and developmental functions. I further discuss insights into the mechanism of receptor activation that have emerged from recent structural and functional studies and consider the interplay between DDRs and other cellular receptors such as integrins. Dysregulation of DDR expression and function is associated with a wide variety of human diseases; this review concludes with a discussion of the DDRs as potential therapeutic targets and their roles in disease progression.