DrBirgit Leitinger
Associate Professor in Matrix Receptor Signalling
National Heart & Lung Institute - Faculty of Medicine
Orcid identifier0000-0003-2426-1179 (opens in a new tab)
- Associate Professor in Matrix Receptor SignallingNational Heart & Lung Institute - Faculty of Medicine
- 020 7594 1591 (Work)
- Room 523, Dr Victor Phillip Dahdaleh (VPD) Building, Hammersmith Campus, United Kingdom
RESEARCH
Background
The discoidin domain receptors, DDR1 and DDR2, are receptor tyrosine kinases that function as collagen receptors. Both DDRs play important roles in developmental processes and a wide range of human diseases, for which only poor treatment options exist. There is a keen interest in anti-DDR drug discovery. However, significant gaps exist in our understanding of the basic mechanism of DDR kinase activation.
Research in the Leitinger lab
Our research has significantly contributed to a better understanding of the activation mechanism of the DDRs. We identified the collagen-binding site in the DDRs (Leitinger, 2003) and established their collagen-binding specificity (Leitinger et al, 2004; Leitinger and Kwan, 2006). We were the first to observe that the DDRs exist as dimers in the absence of ligand binding (Noordeen et al, 2006). This is in stark contrast to typical receptor tyrosine kinases that are thought to exist as monomers that dimerise following ligand binding. The fact that the DDRs are pre-dimerised and exist as constitutive dimers on the cell surface (Xu et al, 2014) established that DDR activation does not conform to the canonical receptor tyrosine kinase activation mechanism.
In collaboration with Richard Farndale, University of Cambridge, we identified specific DDR binding sites in collagens (Konitsiotis et al, 2008; Xu et al, 2011) and discovered that the DDRs promote integrin-mediated cell adhesion to collagen by enhancing integrin activation (Xu et al, 2012). In collaboration with Bassam Ali, United Arab Emirates University, UAE, we described the cellular and biochemical mechanisms underlying a severe human skeletal growth defect caused by missense mutations in DDR2 (Ali et al, 2010; Al-Kindi et al, 2014). In collaboration with Barbara Brodsky, Tufts University, USA, we defined an inhibitory collagen-like DDR ligand (An et al, 2016).
Key structural insight was gained through collaboration with Erhard Hohenester, Imperial College. A crystal structure of the DDR2 discoidin domain in complex with a triple-helical collagen-mimetic peptide defined the sequence-specific collagen recognition of the DDRs (Carafoli et al, 2009). Another crystal structure, in complex with an inhibitory anti-DDR1 antibody fragment (Carafoli et al, 2012) revealed the structure of the discoidin-like domain.
Recent work from our lab established phosphorylation between DDR1 dimers as a key mechanism contributing to DDR1 activation by collagen (Juskaite et al, 2017).
The discoidin domain receptors, DDR1 and DDR2, are receptor tyrosine kinases that function as collagen receptors. Both DDRs play important roles in developmental processes and a wide range of human diseases, for which only poor treatment options exist. There is a keen interest in anti-DDR drug discovery. However, significant gaps exist in our understanding of the basic mechanism of DDR kinase activation.
Research in the Leitinger lab
Our research has significantly contributed to a better understanding of the activation mechanism of the DDRs. We identified the collagen-binding site in the DDRs (Leitinger, 2003) and established their collagen-binding specificity (Leitinger et al, 2004; Leitinger and Kwan, 2006). We were the first to observe that the DDRs exist as dimers in the absence of ligand binding (Noordeen et al, 2006). This is in stark contrast to typical receptor tyrosine kinases that are thought to exist as monomers that dimerise following ligand binding. The fact that the DDRs are pre-dimerised and exist as constitutive dimers on the cell surface (Xu et al, 2014) established that DDR activation does not conform to the canonical receptor tyrosine kinase activation mechanism.
In collaboration with Richard Farndale, University of Cambridge, we identified specific DDR binding sites in collagens (Konitsiotis et al, 2008; Xu et al, 2011) and discovered that the DDRs promote integrin-mediated cell adhesion to collagen by enhancing integrin activation (Xu et al, 2012). In collaboration with Bassam Ali, United Arab Emirates University, UAE, we described the cellular and biochemical mechanisms underlying a severe human skeletal growth defect caused by missense mutations in DDR2 (Ali et al, 2010; Al-Kindi et al, 2014). In collaboration with Barbara Brodsky, Tufts University, USA, we defined an inhibitory collagen-like DDR ligand (An et al, 2016).
Key structural insight was gained through collaboration with Erhard Hohenester, Imperial College. A crystal structure of the DDR2 discoidin domain in complex with a triple-helical collagen-mimetic peptide defined the sequence-specific collagen recognition of the DDRs (Carafoli et al, 2009). Another crystal structure, in complex with an inhibitory anti-DDR1 antibody fragment (Carafoli et al, 2012) revealed the structure of the discoidin-like domain.
Recent work from our lab established phosphorylation between DDR1 dimers as a key mechanism contributing to DDR1 activation by collagen (Juskaite et al, 2017).