Discoidin domain receptor functions in physiological and pathological conditions

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.

Keywords: Cell signaling; Cell–matrix interactions; Receptor activation; Receptor tyrosine kinase; Therapeutic target; Transmembrane collagen receptor.

Figure 1

(A) Schematic structures of DDR1 and DDR2. The extracellular regions are composed of an N-terminal DS domain, followed by a DS-like domain and an extracellular JM region. The cytoplasmic regions contain a large JM region followed by the catalytic tyrosine kinase and a very short C-terminal tail. The plasma membrane is represented by a grey bar. Predicted N-glycosylation sites are depicted by green symbols, predicted O-glycosylation sites are indicated by purple symbols. Four isoforms are shown for DDR1: DDR1a, b, d and e. The cytoplasmic JM regions of DDR1b and DDR1c (not shown) contain additional 37 amino acids (shown in beige for DDR1b) compared with the DDR1a JM region. (B) Alignment of extracellular JM regions of human DDR1 and DDR2. MT1-MMP cleavage sites are highlighted in grey.

Figure 2

Crystal structures of DDR1 globular domains. (A) Cartoon drawing of most of the DDR1 ectodomain bound to collagen, represented by a composite of the DDR2 DS domain bound to a collagen-like peptide (Carafoli et al., 2009) and the structure of the DS and DS-like domain of DDR1 (Carafoli et al., 2012). The side chains of key collagen residues (Met21 of the leading chain, Phe23 of the middle chain) are shown. Disulphide bonds are depicted in yellow. N-linked glycans in the DS-like domain are shown in green. The DDR1 N-terminus is indicated. The dashed line represents the extracellular JM region. (B) Structure of the DDR1 kinase domain in complex with type II inhibitor DDR1-IN-1 (Kim et al., 2013). The inhibitor is depicted in green, tyrosine residues of the activation loop (Tyr792, Tyr796 and Tyr797; DDR1b numbering) are shown in brown. Dashed lines represent loop regions with poor electron density. The dashed line towards the top of the Figure represents the cytoplasmic JM region. The DDR1 C-terminus (Val913) is indicated. The Figure was prepared using the coordinates of PDB entries 2WUH (Carafoli et al., 2009), 4AG4 (Carafoli et al., 2012) and 4BKI (Kim et al., 2013).

Figure 3

Interaction map of phosphotyrosine-based DDR1 interactions. The indicated amino acid numbers refer to the DDR1b isoform; DDR1a lacks Tyr513 and Tyr520. Biochemically verified phosphorylation sites in the JM region and the activation loop of the kinase domain are shown in yellow. The Figure summarizes results obtained mainly from phosphotyrosine peptide pulldowns in human placenta tissue (Lemeer et al., 2012). Only proteins with SH2 or PTB domains are shown. Crk2, adaptor protein Crk2; Nck1/2, adaptor protein Nck1/2; PLC-γ1, phospholipase C γ1; Vav2, guanine nucleotide exchange factor Vav2; RasGAP, negative regulator of Ras; ShcA, SH2 containing transforming protein A; SHIP1/2, SH2 containing inositol polyphosphate 5-phosphatase 1/2; SHP-2, SH2 containing protein tyrosine phosphatase 2; Csk, C-terminal Src kinase; Stat1/3/5b, signal transducer and activator of transcription 1/3/5b; PI3-K, phosphoinositide 3-kinase; SFKs, Src family tyrosine kinases (Yes, Lyn, Fyn).

Figure 4

Selected intracellular events induced by DDR1 binding to collagen. Cellular outcomes depend on the cellular context. In pancreatic cancer cells or mouse embryonic stem cells, DDR1 cooperates with α2β1 in signal transduction, leading to cell scattering/EMT or cell cycle progression, respectively. In MDCK cells, DDR1 antagonises α2β1 functions such as cell spreading and cell migration. In other cell types, such as megakaryocytes or smooth muscle cells, DDR1 promotes cell migration. Solid lines depict direct signalling effectors, dashed blue lines indicate indirect steps. Cellular outcomes in green are processes that are promoted by DDR1 activation, while cellular outcomes in red are suppressed by DDR1 activation.