Discoidin domain-containing receptor 2 explained

Discoidin domain-containing receptor 2, also known as CD167b (cluster of differentiation 167b), is a protein that in humans is encoded by the DDR2 gene.^[1] Discoidin domain-containing receptor 2 is a receptor tyrosine kinase (RTK).

Function

RTKs play a key role in the communication of cells with their microenvironment. These molecules are involved in the regulation of cell growth, differentiation, and metabolism. In several cases the biochemical mechanism by which RTKs transduce signals across the membrane has been shown to be ligand induced receptor oligomerization and subsequent intracellular phosphorylation. In the case of DDR2, the ligand is collagen which binds to its extracellular discoidin domain.^[2] This autophosphorylation leads to phosphorylation of cytosolic targets as well as association with other molecules, which are involved in pleiotropic effects of signal transduction. DDR2 has been associated with a number of diseases including fibrosis and cancer.^[3]

Structure

RTKs have a tripartite structure with extracellular, transmembrane, and cytoplasmic regions. This gene encodes a member of a novel subclass of RTKs and contains a distinct extracellular region encompassing a factor VIII-like domain.^[1]

Gene

Alternative splicing in the 5' UTR of the DDR2 gene results in multiple transcript variants encoding the same protein.^[1]

Interactions

DDR2 (gene) has been shown to interact with SHC1^[4] and phosphorylate Shp2.^[5] DDR2 also interacts with Integrin α₁β₁ and α₂β₁ by promoting their adhesion to collagen.^[6]

Further reading

• Lapsys NM, Layfield R, Baker E, Callen DF, Sutherland GR, Abedinia M, Nixon PF, Mattick JS . Grant Robert Sutherland . Chromosomal location of the human transketolase gene . Cytogenet. Cell Genet. . 61 . 4 . 274–5 . 1992 . 1486804 . 10.1159/000133421 .
• Abedinia M, Layfield R, Jones SM, Nixon PF, Mattick JS . Nucleotide and predicted amino acid sequence of a cDNA clone encoding part of human transketolase . Biochem. Biophys. Res. Commun. . 183 . 3 . 1159–66 . 1992 . 1567394 . 10.1016/S0006-291X(05)80312-2 .
• Edelhoff S, Sweetser DA, Disteche CM . Mapping of the NEP receptor tyrosine kinase gene to human chromosome 6p21.3 and mouse chromosome 17C . Genomics . 25 . 1 . 309–11 . 1995 . 7774938 . 10.1016/0888-7543(95)80144-B .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Karn T, Holtrich U, Bräuninger A, Böhme B, Wolf G, Rübsamen-Waigmann H, Strebhardt K . Structure, expression and chromosomal mapping of TKT from man and mouse: a new subclass of receptor tyrosine kinases with a factor VIII-like domain . Oncogene . 8 . 12 . 3433–40 . 1993 . 8247548 .
• Hillier LD, Lennon G, Becker M, Bonaldo MF, Chiapelli B, Chissoe S, Dietrich N, DuBuque T, Favello A, Gish W, Hawkins M, Hultman M, Kucaba T, Lacy M, Le M, Le N, Mardis E, Moore B, Morris M, Parsons J, Prange C, Rifkin L, Rohlfing T, Schellenberg K, Bento Soares M, Tan F, Thierry-Meg J, Trevaskis E, Underwood K, Wohldman P, Waterston R, Wilson R, Marra M . Generation and analysis of 280,000 human expressed sequence tags . Genome Res. . 6 . 9 . 807–28 . 1996 . 8889549 . 10.1101/gr.6.9.807 . free .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Vogel W, Gish GD, Alves F, Pawson T . The discoidin domain receptor tyrosine kinases are activated by collagen . Mol. Cell . 1 . 1 . 13–23 . 1997 . 9659899 . 10.1016/S1097-2765(00)80003-9 . free .
• Mohan RR, Mohan RR, Wilson SE . Discoidin domain receptor (DDR) 1 and 2: collagen-activated tyrosine kinase receptors in the cornea . Exp. Eye Res. . 72 . 1 . 87–92 . 2001 . 11133186 . 10.1006/exer.2000.0932 .
• Ikeda K, Wang LH, Torres R, Zhao H, Olaso E, Eng FJ, Labrador P, Klein R, Lovett D, Yancopoulos GD, Friedman SL, Lin HC . Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen . J. Biol. Chem. . 277 . 21 . 19206–12 . 2002 . 11884411 . 10.1074/jbc.M201078200 . free .
• Faraci E, Eck M, Gerstmayer B, Bosio A, Vogel WF . An extracellular matrix-specific microarray allowed the identification of target genes downstream of discoidin domain receptors . Matrix Biol. . 22 . 4 . 373–81 . 2003 . 12935821 . 10.1016/S0945-053X(03)00053-2 .
• Ferri N, Carragher NO, Raines EW . 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. . 164 . 5 . 1575–85 . 2004 . 15111304 . 1615659 . 10.1016/S0002-9440(10)63716-9 .
• Leitinger B, Steplewski A, Fertala A . The D2 period of collagen II contains a specific binding site for the human discoidin domain receptor, DDR2 . J. Mol. Biol. . 344 . 4 . 993–1003 . 2004 . 15544808 . 10.1016/j.jmb.2004.09.089 .
• Wall SJ, Werner E, Werb Z, DeClerck YA . Discoidin domain receptor 2 mediates tumor cell cycle arrest induced by fibrillar collagen . J. Biol. Chem. . 280 . 48 . 40187–94 . 2005 . 16186104 . 2768768 . 10.1074/jbc.M508226200 . free .
• Yang K, Kim JH, Kim HJ, Park IS, Kim IY, Yang BS . Tyrosine 740 phosphorylation of discoidin domain receptor 2 by Src stimulates intramolecular autophosphorylation and Shc signaling complex formation . J. Biol. Chem. . 280 . 47 . 39058–66 . 2005 . 16186108 . 10.1074/jbc.M506921200 . free .
• Leitinger B, Kwan AP . The discoidin domain receptor DDR2 is a receptor for type X collagen . Matrix Biol. . 25 . 6 . 355–64 . 2006 . 16806867 . 10.1016/j.matbio.2006.05.006 .
• Zhang W, Ding T, Zhang J, Su J, Li F, Liu X, Ma W, Yao L . Expression of discoidin domain receptor 2 (DDR2) extracellular domain in pichia pastoris and functional analysis in synovial fibroblasts and NIT3T3 cells . Mol. Cell. Biochem. . 290 . 1–2 . 43–53 . 2006 . 16967187 . 10.1007/s11010-006-9136-4 . 19400659 .
• Ford CE, Lau SK, Zhu CQ, Andersson T, Tsao MS, Vogel WF . Expression and mutation analysis of the discoidin domain receptors 1 and 2 in non-small cell lung carcinoma . Br. J. Cancer . 96 . 5 . 808–14 . 2007 . 17299390 . 2360060 . 10.1038/sj.bjc.6603614 .
• Xu L, Servais J, Polur I, Kim D, Lee PL, Chung K, Li Y . Attenuation of osteoarthritis progression by reduction of discoidin domain receptor 2 in mice . Arthritis Rheum. . 62 . 9 . 2736–44 . 2010 . 20518074 . 2946478 . 10.1002/art.27582 .

Notes and References

1. Web site: Entrez Gene: DDR2 discoidin domain receptor family, member 2.
2. Fu HL, Valiathan RR, Arkwright R, Sohail A, Mihai C, Kumarasiri M, Mahasenan KV, Mobashery S, Huang P, Agarwal G, Fridman R . Discoidin domain receptors: unique receptor tyrosine kinases in collagen-mediated signaling . J. Biol. Chem. . 288 . 11 . 7430–7 . March 2013 . 23335507 . 3597784 . 10.1074/jbc.R112.444158 . free .
3. Leitinger B . Transmembrane collagen receptors . Annu. Rev. Cell Dev. Biol. . 27 . 265–90 . May 2011 . 21568710 . 10.1146/annurev-cellbio-092910-154013 .
4. Ikeda K, Wang LH, Torres R, Zhao H, Olaso E, Eng FJ, Labrador P, Klein R, Lovett D, Yancopoulos GD, Friedman SL, Lin HC . Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen . J. Biol. Chem. . 277 . 21 . 19206–12 . May 2002 . 11884411 . 10.1074/jbc.M201078200 . free .
5. Iwai LK, Payne LS, Luczynski MT, Chang F, Xu H, Clinton RW, Paul A, Esposito EA, Gridley S, Leitinger B, Naegle KM, Huang PH . Phosphoproteomics of collagen receptor networks reveals SHP-2 phosphorylation downstream of wild-type DDR2 and its lung cancer mutants . Biochem. J. . 454 . 3 . 501–13 . July 2013 . 23822953 . 3893797 . 10.1042/BJ20121750 .
6. Xu H, Bihan D, Chang F, Huang PH, Farndale RW, Leitinger B . Discoidin domain receptors promote α1β1- and α2β1-integrin mediated cell adhesion to collagen by enhancing integrin activation . PLOS ONE . 7 . 12 . e52209 . Dec 2012 . 23284937 . 3527415 . 10.1371/journal.pone.0052209 . 2012PLoSO...752209X . free .