Chapter Two - Discoidin Domain Receptor Functions in Physiological and Pathological Conditions
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 cell cycle 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.
Section snippets
Expression and Tissue Functions of DDRs
The DDRs are widely expressed in different tissues, both during development and in adult organisms. DDR1 mRNA is found in many tissues in mice and humans, with high levels in brain, lung, kidney, spleen, and placenta (Di Marco et al., 1993, Johnson et al., 1993, Laval et al., 1994, Perez et al., 1994, Perez et al., 1996). DDR2 mRNA is high in skeletal and heart muscle, kidney, and lung (Karn et al., 1993, Lai and Lemke, 1994). Both DDRs are expressed in the developing nervous system (Lai and
Genomic structure and transcriptional regulation
The DDR cDNAs were isolated by several groups in the 1990s based on homology cloning with the intention to discover novel RTK gene products (Alves et al., 1995, Di Marco et al., 1993, Johnson et al., 1993, Karn et al., 1993, Lai and Lemke, 1994, Laval et al., 1994, Perez et al., 1994, Perez et al., 1996, Sanchez et al., 1994, Zerlin et al., 1993). While the kinase domain of the encoded proteins were noted to be about 45% identical to that of the neurotrophin receptor, TrkA, their extracellular
Mechanism of receptor activation
The fist step in transmembrane signal transduction of RTKs manifests itself as autophosphorylation of cytoplasmic tyrosine residues. A requirement for this is the generation of receptor dimers (Lemmon and Schlessinger, 2010). In the absence of ligand, typical RTKs are thought to exist as monomers or be in equilibrium with a small amount of inactive dimers. Ligand binding to RTKs induces dimer formation and the resulting conformational changes in the dimer bring the kinase domains into close
DDR Functions During Development
Both DDRs play key roles in development, with DDR1 important in organogenesis and DDR2 in bone growth. As mentioned above, DDR1 expression is mainly found in epithelial cells, in particular in the kidney, lung, gastrointestinal tract, and brain, while DDR2 is found in cells of connective tissue (Alves et al., 1995), including fibroblasts of different origins and bone cells such as chondrocytes and osteoblasts.
Signaling pathways activated by DDRs
Ligand binding to RTKs leads to phosphorylation of distinct cytoplasmic tyrosine residues, which serve as docking sites for the assembly of downstream signaling molecules that are recruited to the receptor (Lemmon and Schlessinger, 2010). DDR1b and DDR1c have 15 tyrosine residues in their cytosolic domain (Fig. 2.3), while DDR1a has 13 and DDR2 14. All of these tyrosines could function as potential ligand-induced phosphotyrosine sites that act as docking sites for signaling adaptors. However,
DDRs as Potential Therapeutic Targets in Disease
Both DDRs have been linked to a wide variety of human disorders, ranging from fibrotic disorders of different organs, atherosclerosis, arthritis, and many types of cancers. Targeted deletion of DDRs in mice and the use of a number of mouse models of chronic human diseases have helped to unravel DDR functions in disease progression. The DDRs usually play positive roles in pathologies, and the use of DDR inhibitors is therefore an attractive therapeutic approach, in particular for diseases that
Conclusions
Since collagens were first identified as ligands for the DDRs, we have gained a good understanding of the structural basis of ligand recognition. We also have gained many insights into the in vivo functions of DDRs and the roles they play in development and disease. However, many mysteries remain about some of the most fundamental DDR characteristics and compared with most RTK families the DDRs remain under-researched. As outlined above, both DDRs are potential drug targets for a number of
Acknowledgments
I thank Erhard Hohenester for critical reading of this manuscript and for providing Fig. 2.2. I acknowledge funding from the Medical Research Council UK (Grant G0701121) and the Biotechnology and Biological Sciences Research Council UK (Grant BB/I011226/1).
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