DDR2

DDR2 Full Name

discoidin domain receptor tyrosine kinase 2

DDR2 Introduction

DDR2 encodes discoidin domain receptor 2, one of only two receptor tyrosine kinases that are activated by collagen, the most abundant protein of the extracellular matrix. Whereas most receptor tyrosine kinases respond to soluble growth factors, the discoidin domain receptors are unique in recognizing the structural collagen triple helix, and they thereby allow cells to sense and respond to their surrounding matrix. When collagen binds the extracellular discoidin domain of DDR2, the receptor dimerizes and its intracellular kinase domain autophosphorylates, initiating signaling cascades that regulate cell proliferation, migration, differentiation, and the remodeling of the matrix itself. DDR2 is expressed in mesenchymal cells such as fibroblasts, chondrocytes, osteoblasts, and smooth muscle cells, and it is essential for normal skeletal development: gain-of-function mutations in DDR2 cause a rare form of dwarfism known as spondylo-meta-epiphyseal dysplasia, while mice lacking the receptor have short limbs and defects in bone growth. In disease, DDR2 has attracted attention for two principal reasons. First, it drives the pathological accumulation of collagen in fibrosis of the lung, liver, and other organs. Second, it promotes the invasion and metastasis of several cancers, and mutations or overexpression of DDR2 have been identified in lung squamous cell carcinoma and other tumors, where the kinase may be therapeutically targetable. DDR2 thereby exemplifies how a receptor for an abundant matrix protein can link tissue architecture to both development and disease.

Figure 1. The structure of DDR2.

Receptor Architecture, Collagen Recognition, and Kinase Activation
DDR2 is a single-pass transmembrane receptor tyrosine kinase whose extracellular region contains an N-terminal discoidin domain, the module that binds the collagen triple helix.
A discoidin-like domain adjacent to the ligand-binding domain assists in collagen recognition, and the juxtamembrane region carries regulatory tyrosine residues whose phosphorylation controls kinase activity.
Collagen binding promotes receptor dimerization and the trans-autophosphorylation of tyrosine residues in the kinase domain and juxtamembrane region, creating docking sites for downstream signaling proteins.
Unlike most receptor tyrosine kinases, which activate within seconds, DDR2 activation by collagen is slow and sustained, reflecting the unusual nature of its ligand and the requirement for receptor clustering.
The DDR2 gene is located on human chromosome 1, and the receptor is expressed predominantly in cells of mesenchymal origin, including fibroblasts, chondrocytes, and vascular smooth muscle cells.
Downstream of the receptor, signaling pathways such as the Src family kinases, SHC, and the MAP kinase cascade are engaged, leading to changes in gene expression that control cell behavior and matrix turnover.
DDR2 can also interact with integrins and with matrix metalloproteinases, placing it within a larger network that couples matrix sensing to tissue remodeling.

Skeletal Development, Fibrosis, and Cancer
In the growth plate, DDR2 is required for the proliferation and differentiation of chondrocytes, and mice lacking the receptor develop dwarfism with shortened bones, mirroring the skeletal phenotype of patients with DDR2 mutations.
Dominant mutations in DDR2 cause spondylo-meta-epiphyseal dysplasia, a rare autosomal dominant disorder characterized by short stature, abnormal vertebrae, and premature calcification of the intervertebral discs.
In fibrosis, DDR2 expression is upregulated in activated myofibroblasts, and collagen-stimulated DDR2 signaling promotes their proliferation and the excessive deposition of extracellular matrix in the lungs, liver, kidneys, and heart.
DDR2 also regulates the production of matrix metalloproteinases, and through this activity it can either promote the matrix remodeling that accompanies fibrosis or facilitate the invasion of tumor cells through degraded tissue barriers.
In cancer, DDR2 is overexpressed or mutated in a subset of tumors, including lung squamous cell carcinoma, head and neck cancer, and breast cancer, where it enhances tumor cell migration, invasion, and metastasis.
Because DDR2 is a kinase, it is amenable to inhibition by small-molecule drugs, and several kinase inhibitors that target DDR2 have shown activity against DDR2-dependent tumor cells, supporting the evaluation of DDR2 as a therapeutic target in fibrosis and malignancy.

Alternate Names for DDR2

DDR2; discoidin domain receptor tyrosine kinase 2; TKT; MIG20a; NTRKR3; TYRO10; discoidin domain-containing receptor 2; tyrosylprotein kinase; hydroxyaryl-protein kinase; discoidin domain receptor 2