About Discoidin Domain Receptor Tyrosine Kinase / DDRs:
Discoidin domain receptors (DDRs) are tyrosine kinases. They recognize collagens as their ligands. There are two members of the DDR family, DDR1 and DDR2. DDRs are unique in their structural features and have distinctive activation kinetics. They stand out from others in the kinase superfamily. One of their functions is to regulate cell-collagen interactions, which means they are beginning to be employed as major sensors of collagen matrices and potential novel therapeutic targets.
DDRs Function
Receptor tyrosine kinases (RTKs) contribute to cell communication within their microenvironment. They help to regulate cell growth, differentiation and metabolism. The protein encoded by the gene is activated by different types of collagen and is part of a subfamily of tyrosine kinase receptor. DDR1 is expressed in epithelial cells, particularly in the kidney, lung, gastrointestinal tract, and the brain. Overexpression can also be found in a number of tumours in humans, including breast, ovarian and esophageal tumours. DDR2 has also been associated with different conditions, such as fibrosis and cancer.
DDRs undergo tyrosine autophosphorylation when collagen binding and have distinctive activation kinetics. They regulate various cell-collagen interactions. There are five membrane-anchored isoforms in the DDR1 subfamily, which are generated by alternative splicing. The DDR2 subfamily has a single protein. All DDRs, apart from two secreted DDR1 isoforms, are single-pass type I transmembrane glycoproteins. They are characterized by the presence of six distinct protein domains. These are a discoidin (DS) domain, a DS-like domain, an extracellular juxtamembrane (EJXM) region, a transmembrane (TM) segment, a long IJXM region, and an intracellular KD. N-terminal DS and DS-like domains define the DDR RTK subfamily.
Discoidin Domain Receptor Tyrosine Kinase Mechanism
DDR1 and DDR2 bind to and are activated by fibrillar collagens I-III and V, while only DDR1 is activated by the basement membrane collagen IV. However, non-fibrillar collagen X primarily activates DDR2. A number of binding sites have been identified for DDR1 and DDR2 in collagens II and III. DDR-deficient mice show that DDRs are important as collagen receptors, showing skeletal abnormalities and reproductive abnormalities. DDRs are also shown to be important in inflammatory and fibrotic responses in some conditions.
DDRs undergo tyrosine autophosphorylation upon collagen binding. However, while classical RTKs undergo tyrosine autophosphorylation in just a few seconds, DDRs can take minutes or even hours to achieve the same thing. After receptor activation, phosphorylation levels persist for days in DDRs, whereas many classical RTKs undergo negative regulation via mechanisms such as receptor/ligand internalization and subsequent degradation or dephosphorylation by phosphatases.
DDRs Interactions
Evidence suggests that DDRs are key in cancer progression. They play an important role by regulating the interactions of tumour cells with their surrounding collagen matrix. DDRs are taken over by tumour cells when cancer occurs, which means that standard cell-matrix communication is disrupted, while pro-migratory and pro-invasive programs are activated. The role of DDRs in cancer progression could be complex and is not yet entirely understood, and they could either promote or suppress tumour cell behaviour. More research is required into DDRs to discover if these RTKs could become novel therapeutic targets in cancer.