Biology of Matrix-Activated Receptors
Dr Birgit Leitinger, Head of Group
We are interested in defining the molecular mechanism of receptor activation for the receptor tyrosine kinases DDR1 and DDR2. The DDRs are widely expressed, and, uniquely among receptor tyrosine kinases, activated by the extracellular matrix protein collagen. The DDRs play important roles in developmental processes and human disease. The DDR activation mechanism differs from that of canonical RTKs. Our work thus provides the framework for drug design against unwanted DDR signalling in diseases such as lung fibrosis, atherosclerosis, arthritis and cancer.
Recent research from our lab
- DDRs are predimerised in the absence of ligand, unlike conventional receptor tyrosine kinases, which are thought to dimerise only upon ligand binding
- Identification of a leuzine zipper motif in the DDR1 transmembrane domain that is essential for transmembrane signalling
- Identification and characterisation of specific DDR binding motifs in collagen (in collaboration with Prof R Farndale, University of Cambridge)
- Structural analysis of collagen recognition by the DDR2 discoidin domain (in collaboration with Prof E Hohenester, Imperial College London)
- Creation of signal-blocking anti-DDR1 antibodies
- Structural analysis of DDR1 extracellular region bound to inhibitory Fab fragment (in collaboration with Prof E Hohenester, Imperial College London)
- Cellular and biochemical mechanisms underlying DDR2 missense mutations that cause a human skeletal growth defect called SMED-SL (in collaboration with Dr B Ali, United Arab Emirates University, Al-Ain, UAE)
-
Selected Publications
Carafoli, F, Mayer, MC, Shiraishi, K, Pecheva, MA, Chan, LY, Nan, R, Leitinger, B, & Hohenester, E (2012) Structure of the discoidin domain receptor 1 extracellular region bound to an inhibitory Fab fragment reveals features important for signaling. Structure, 20, 688-97.
Leitinger, B (2011). Transmembrane Collagen Receptors. Annu Rev Cell Dev Biol, 27: 265-290 (invited review)
Ali, BR, Xu, H, Akawi, NA, John, A, Karuvantevida, NS, Langer, R, Al-Gazali, L & Leitinger, B (2010). 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. 19:2239-2250.
Konitsiotis AD, Raynal N, Bihan D, Hohenester E, Farndale RW, & Leitinger B (14 Mar 2008). Characterization of high affinity binding motifs for the discoidin domain receptor DDR2 in collagen. J Biol Chem. 283:6861-6868. Selected as Paper of the week
