Chapter Two - Discoidin Domain Receptor Functions in Physiological and Pathological Conditions

https://doi.org/10.1016/B978-0-12-800180-6.00002-5Get rights and content

Abstract

The discoidin domain receptors, DDR1 and DDR2, are nonintegrin collagen receptors that are members of the receptor tyrosine kinase family. Both DDRs bind a number of different collagen types and play important roles in embryo development. Dysregulated DDR function is associated with progression of various human diseases, including fibrosis, arthritis, and cancer. By interacting with key components of the extracellular matrix and displaying distinct activation kinetics, the DDRs form a unique subfamily of receptor tyrosine kinases. DDR-facilitated cellular functions include cell migration, cell survival, proliferation, and differentiation, as well as remodeling of extracellular matrices. This review summarizes the current knowledge of DDR–ligand interactions, DDR-initiated signal pathways and the molecular mechanisms that regulate receptor function. Also discussed are the roles of DDRs in development and disease progression.

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).

References (181)

  • F. Carafoli et al.

    Crystallographic insight into collagen recognition by discoidin domain receptor 2

    Structure

    (2009)
  • F. Carafoli et al.

    Structure of the discoidin domain receptor 1 extracellular region bound to an inhibitory Fab fragment reveals features important for signaling

    Structure

    (2012)
  • J. Chen et al.

    The a2 integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis

    Am. J. Pathol.

    (2002)
  • S.C. Chen et al.

    Hypoxia induces discoidin domain receptor-2 expression via the p38 pathway in vascular smooth muscle cells to increase their migration

    Biochem. Biophys. Res. Commun.

    (2008)
  • P.M. Comoglio et al.

    Interactions between growth factor receptors and adhesion molecules: breaking the rules

    Curr. Opin. Cell Biol.

    (2003)
  • C.A. Curat et al.

    Mapping of epitopes in discoidin domain receptor 1 critical for collagen binding

    J. Biol. Chem.

    (2001)
  • E. Day et al.

    Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib

    Eur. J. Pharmacol.

    (2008)
  • E. Di Marco et al.

    Molecular cloning of trkE, a novel trk-related putative tyrosine kinase receptor isolated from normal human keratinocytes and widely expressed by normal human tissues

    J. Biol. Chem.

    (1993)
  • S. Edelhoff et al.

    Mapping of the NEP receptor tyrosine kinase gene to human chromosome 6p21.3 and mouse chromosome 17C

    Genomics

    (1995)
  • N. Ferri et al.

    Role of discoidin domain receptors 1 and 2 in human smooth muscle cell-mediated collagen remodeling: potential implications in atherosclerosis and lymphangioleiomyomatosis

    Am. J. Pathol.

    (2004)
  • L.A. Flynn et al.

    Inhibition of collagen fibrillogenesis by cells expressing soluble extracellular domains of DDR1 and DDR2

    J. Mol. Biol.

    (2010)
  • H.L. Fu et al.

    Shedding of discoidin domain receptor 1 by membrane-type matrix metalloproteinases

    J. Biol. Chem.

    (2013)
  • O. Gross et al.

    DDR1-deficient mice show localized subepithelial GBM thickening with focal loss of slit diaphragms and proteinuria

    Kidney Int.

    (2004)
  • O. Gross et al.

    Loss of collagen-receptor DDR1 delays renal fibrosis in hereditary type IV collagen disease

    Matrix Biol.

    (2010)
  • D. Guerrot et al.

    Discoidin domain receptor 1 is a major mediator of inflammation and fibrosis in obstructive nephropathy

    Am. J. Pathol.

    (2011)
  • L.N. Hachehouche et al.

    Implication of discoidin domain receptor 1 in T cell migration in three-dimensional collagen

    Mol. Immunol.

    (2010)
  • H.N. Hilton et al.

    KIBRA interacts with discoidin domain receptor 1 to modulate collagen-induced signalling

    Biochim. Biophys. Acta

    (2008)
  • D.W. Holt et al.

    Osteoarthritis-like changes in the heterozygous sedc mouse associated with the HtrA1-Ddr2-Mmp-13 degradative pathway: a new model of osteoarthritis

    Osteoarthr. Cartil.

    (2012)
  • G. Hou et al.

    Deletion of discoidin domain receptor 2 does not affect smooth muscle cell adhesion, migration, or proliferation in response to type I collagen

    Cardiovasc. Pathol.

    (2012)
  • R. Hynes

    Integrins. Bidirectional, allosteric signaling machines

    Cell

    (2002)
  • K. Ikeda et al.

    Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen

    J. Biol. Chem.

    (2002)
  • N. Jura et al.

    Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment

    Cell

    (2009)
  • R. Khosravi et al.

    Collagen advanced glycation inhibits its discoidin domain receptor 2 (DDR2)-mediated induction of lysyl oxidase in osteoblasts

    Bone

    (2014)
  • A. Kiedzierska et al.

    Structural similarities and functional diversity of eukaryotic discoidin-like domains

    Biochim. Biophys. Acta

    (2007)
  • H.G. Kim et al.

    DDR1 receptor tyrosine kinase promotes prosurvival pathway through Notch1 activation

    J. Biol. Chem.

    (2011)
  • A.D. Konitsiotis et al.

    Characterization of high affinity binding motifs for the discoidin domain receptor DDR2 in collagen

    J. Biol. Chem.

    (2008)
  • D.H. Koo et al.

    Pinpointing phosphotyrosine-dependent interactions downstream of the collagen receptor DDR1

    FEBS Lett.

    (2006)
  • B. Leitinger

    Molecular analysis of collagen binding by the human discoidin domain receptors, DDR1 and DDR2. Identification of collagen binding sites in DDR2

    J. Biol. Chem.

    (2003)
  • B. Leitinger et al.

    The discoidin domain receptor DDR2 is a receptor for type X collagen

    Matrix Biol.

    (2006)
  • B. Leitinger et al.

    The D2 period of collagen II contains a specific binding site for the human discoidin domain receptor, DDR2

    J. Mol. Biol.

    (2004)
  • S. Lemeer et al.

    Phosphotyrosine mediated protein interactions of the discoidin domain receptor 1

    J. Proteomics

    (2012)
  • M.A. Lemmon et al.

    Cell signaling by receptor tyrosine kinases

    Cell

    (2010)
  • K.K. Lu et al.

    Collagen stimulates discoidin domain receptor 1-mediated migration of smooth muscle cells through Src

    Cardiovasc. Pathol.

    (2011)
  • G. Agarwal et al.

    Binding of discoidin domain receptor 2 to collagen I: an atomic force microscopy investigation

    Biochemistry

    (2002)
  • B.R. Ali et al.

    Trafficking defects and loss of ligand binding are the underlying causes of all reported DDR2 missense mutations found in SMED-SL patients

    Hum. Mol. Genet.

    (2010)
  • F. Alves et al.

    Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer

    Oncogene

    (1995)
  • F. Alves et al.

    Identification of two novel, kinase-deficient variants of discoidin domain receptor 1: differential expression in human colon cancer cell lines

    Faseb J.

    (2001)
  • J. Arribas et al.

    Protein ectodomain shedding

    Chem. Rev.

    (2002)
  • C. Avivi-Green et al.

    Discoidin domain receptor 1-deficient mice are resistant to bleomycin-induced lung fibrosis

    Am. J. Respir. Crit. Care Med.

    (2006)
  • K.T. Barker et al.

    Expression patterns of the novel receptor-like tyrosine kinase, DDR, in human breast tumours

    Oncogene

    (1995)
  • Cited by (273)

    View all citing articles on Scopus
    View full text