Imperial College London

DrBirgitLeitinger

Faculty of MedicineNational Heart & Lung Institute

Reader in Matrix Receptor Signalling
 
 
 
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Contact

 

+44 (0)20 7594 1591b.leitinger Website

 
 
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Location

 

115Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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68 results found

Sammon D, Hohenester E, Leitinger B, 2021, Two-step release of kinase autoinhibition in discoidin domain receptor 1 (vol 117, 22051, 2020), PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 118, ISSN: 0027-8424

Journal article

Sammon D, Hohenester E, Leitinger B, 2020, Two-step release of kinase autoinhibition in discoidin domain receptor 1, Proceedings of the National Academy of Sciences of USA, Vol: 117, Pages: 22051-22060, ISSN: 0027-8424

Discoidin domain receptor1 (DDR1)is a collagen-activated receptor tyrosine kinase with important functions in organogenesis and tissue homeostasis.Aberrant DDR1activity contributes to the progression of human diseases, including fibrosis and cancer. How DDR1 activity is regulated is poorly understood. We investigated the function of the long intracellular juxtamembrane (JM) region of human DDR1 and found that the kinase-proximal segment, JM4, is an important regulator of kinase activity.Crystal structure analysis revealed that JM4 forms a hairpin that penetrates the kinase active site, reinforcing autoinhibition by the activation loop. Using in vitro enzymology with soluble kinase constructs, we established that release from autoinhibition occurs in two distinct steps:rapid autophosphorylation of the JM4 tyrosines, Tyr569 and Tyr586, followed by slower autophosphorylation of activation loop tyrosines. Mutation of JM4 tyrosines abolished collagen-induced DDR1 activation in cells.The new insights may be used to develop allosteric, DDR1-specific,kinase inhibitors.

Journal article

Jalan A, Sammon D, Hartgerink J, Brear P, Stott K, Hamaia S, Hunter E, Walker D, Leitinger B, Farndale Ret al., 2020, Chain alignment of collagen I deciphered using computationally designed heterotrimers, Nature Chemical Biology, Vol: 16, Pages: 423-429, ISSN: 1552-4450

The most abundant member of the collagen protein family, collagen I (COL1), is composed of two similar (chain A) and one unique (chain B) polypeptides that self-assemble with one amino acid offset into a heterotrimeric triple helix. Given the offset, chain B can occupy either the leading (BAA), middle (ABA) or trailing (AAB) position of the triple helix, yielding three isomeric biomacromolecules with different protein recognition properties. Despite five decades of intensive research, there is no consensus on the position of chain B in COL1. Here, three triple-helical heterotrimers that each contained a putative Von Willebrand Factor (VWF) and discoidin domain receptor (DDR) recognition sequence from COL1 were designed with chain B permutated in all three positions. AAB demonstrated a strong preference for both VWF and DDR and also induced higher levels of cellular DDR phosphorylation. Thus, we resolve this long-standing mystery and show that COL1 adopts an AAB register.

Journal article

Auguste P, Leitinger B, Liard C, Rocher V, Azema L, Saltel F, Santamaria Det al., 2020, Meeting report - first discoidin domain receptors meeting, Journal of Cell Science, Vol: 133, ISSN: 0021-9533

For the first time, a meeting dedicated to the tyrosine kinase receptors DDR1 and DDR2 took place in Bordeaux, a famous and historical city in the south of France. Over the course of 3 days, the meeting allowed 60 participants from 11 different countries to exchange ideas and their new findings about these unique collagen receptors, focusing on their role in various physiological and pathological conditions and addressing their mechanisms of regulation and signalling. The involvement of these receptors in different pathologies was also considered, with emphasis on cancer development and potential therapeutic applications. Here, we summarize the key elements of this meeting.

Journal article

Corcoran D, Juskaite V, Xu Y, Gorlitz F, Alexandrov Y, Dunsby C, French P, Leitinger Bet al., 2019, DDR1 autophosphorylation is a result of aggregation into dense clusters, Scientific Reports, Vol: 9, ISSN: 2045-2322

The collagen receptor DDR1 is a receptor tyrosine kinase that promotes progression ofa wide range of human disorders. Little is known about how ligand binding triggers DDR1 kinase activity. We previously reported that collagen induces DDR1 activation through lateral dimer association and phosphorylation between dimers, a process that requires specific transmembrane association. Here we demonstrate ligand-induced DDR1 clustering by widefield and super-resolution imaging and provide evidence for a mechanism whereby DDR1 kinase activity is determined by its molecular density. Ligand binding resulted in initial DDR1 reorganisation into morphologically distinct clusters with unphosphorylated DDR1. Further compaction over time led to clusters with highly aggregated and phosphorylated DDR1. Ligand-induced DDR1 clustering was abolished by transmembrane mutations but did not require kinase activity. Our results significantly advance our understanding of the molecular events underpinning ligand-induced DDR1 kinase activity and provide an explanation for the unusually slow DDR1 activation kinetics.

Journal article

Eckes B, Sawant MS, Leitinger B, Krieg Tet al., 2019, Cell - collagen interactions through collagen-binding integrins are dispensable for murine development, 49th Annual Meeting of the European-Society-for-Dermatological-Research (ESDR), Publisher: ELSEVIER SCIENCE INC, Pages: S325-S325, ISSN: 0022-202X

Conference paper

Juskaite V, Leitinger B, 2019, Cell-based assay for recruitment of DDR1 to collagen-coated beads, Bio-protocol, Vol: 9, ISSN: 2331-8325

The discoidin domain receptors, DDR1 and DDR2, are key signaling receptors for theextracellular matrix protein collagen. The interactions of cells with collagen are difficult to study becauseof the difficulty to obtain native collagen fibers for in vitro studies. Thus, in vitro studies often use acidsoluble collagens in the form of single triple helices, which are not representative of the densely packedinsoluble collagen fibers found in tissues. In this protocol, we describe a method that allows stimulatingDDR1 locally with collagen-coated beads. Latex beads are first coated with acid-soluble collagen, thenadded to cells expressing DDR1. Recruitment of DDR1 to the beads and collagen-induced DDR1phosphorylation is visualized by immunofluorescence microscopy on a widefield microscope. In thismethod, densely packed collagen is presented to cells in an insoluble form. Bead coating is easy toperform, and this method thus presents a straightforward protocol with which to study local recruitmentof collagen receptors to insoluble collagen.

Journal article

Sammon D, Hohenester E, Leitinger B, 2019, The regulation of DDR1 catalysis by its intracellular juxtamembrane region, Spring Meeting of the British-Society-for-Matrix-Biology (BSMB) on Stroma, Niche and Repair, Publisher: WILEY, Pages: A33-A33, ISSN: 0959-9673

Conference paper

Vehlow A, Klapproth E, Jin S, Hannen R, Hauswald M, Bartsch J-W, Nimsky C, Temme A, Leitinger B, Cordes Net al., 2019, Interaction of the Discoidin Domain Receptor 1 with the 14-3-3/Akt/ Beclin 1 Complex modulates the Glioblastoma Therapeutic Sensibility, 25th Annual Meeting of the German-Society-of-Radiation-Oncology (DEGRO), Publisher: SPRINGER HEIDELBERG, Pages: S43-S44, ISSN: 0179-7158

Conference paper

Vehlow A, Klapproth E, Jin S, Hannen R, Hauswald M, Bartsch J-W, Nimsky C, Temme A, Leitinger B, Cordes Net al., 2019, Interaction of discoidin domain receptor 1 with a 14-3-3-Beclin-Akt1 complex modulates glioblastoma therapy sensitivity, Cell Reports, Vol: 26, Pages: 3672-3683, ISSN: 2211-1247

Glioblastoma (GBM) is highly refractory to therapy and associated with poor clinical outcome. Here, we reveal a critical function of the promitotic and adhesion-mediating discoidin domain receptor 1 (DDR1) in modulating GBM therapy resistance. In GBM cultures and clinical samples, we show a DDR1 and GBM stem cell marker co-expression that correlates with patient outcome. We demonstrate that inhibition of DDR1 in combination with radiochemotherapy with temozolomide in GBM models enhances sensitivity and prolongs survival superior to conventional therapy. We identify a 14-3-3-Beclin-1-Akt1 protein complex assembling with DDR1 to be required for prosurvival Akt and mTOR signaling and regulation of autophagy-associated therapy sensitivity. Our results uncover a mechanism driven by DDR1 that controls GBM therapy resistance and provide a rationale target for the development of therapy-sensitizing agents.

Journal article

Corcoran D, Juskaite V, Leitinger B, 2018, High-affinity collagen binding and signalling requires clustering of DDR1 in the cell membrane, Matrix Biology Europe Meeting, Publisher: WILEY, Pages: A11-A11, ISSN: 0959-9673

Conference paper

Malcor J-D, Juskaite V, Gavriilidou D, Hunter E, Davidenko N, Hamaia S, Sinha S, Cameron R, Best S, Leitinger B, Farndale Ret al., 2018, Coupling of a specific photoreactive triple-helical peptide to crosslinked collagen films restores binding and activation of DDR2 and VWF, Biomaterials, Vol: 182, Pages: 21-34, ISSN: 0142-9612

Collagen-based scaffolds may require chemical crosslinking to achieve mechanical properties suitable for tissue engineering. Carbodiimide treatment, often used for this purpose, consumes amino acid side chains required for receptor recognition, thus reducing cell–collagen interaction. Here, we restore recognition and function of both von Willebrand Factor (VWF) and Discoidin Domain Receptor 2 (DDR2) to crosslinked collagen films by derivatisation with a specific triple-helical peptide (THP), an approach previously applied to integrin-mediated cellular adhesion. The THP contained the collagen III-derived active sequence, GPRGQOGVNleGFO, conjugated to a photoreactive moiety, diazirine, allowing UV-dependent covalent coupling to collagen films. Crosslinking of collagen films attenuated the binding of recombinant VWF A3 domain and of DDR2 (as the GST and Fc fusions, respectively), and coupling of the specific THP restored their attachment. These derivatised films supported activation of DDR2 expressed in either COS-7 or HEK293 cells, reflected by phosphorylation of tyrosine 740, and VWF-mediated platelet deposition from flowing blood was restored. Further, such films were able to increase low-density lipoprotein uptake in vascular endothelial cells, a marker for endothelial phenotype. Thus, covalent linkage of specific THPs to crosslinked collagen films i) restores their cognate protein binding, ii) triggers the corresponding cellular responses, and iii) demonstrates the broad applicability of the approach to a range of receptors for applications in regenerative medicine.

Journal article

Leitinger B, Saltel F, 2018, Discoidin domain receptors: multitaskers for physiological and pathological processes, Cell Adhesion and Migration, Vol: 12, Pages: 398-399, ISSN: 1933-6926

Journal article

Juskaite V, Corcoran D, Leitinger B, 2017, Collagen induces activation of DDR1 through lateral dimer association and phosphorylation between dimers, Autumn Meeting of the British-Society-for-Matrix-Biology (BSMB), Publisher: Wiley, Pages: A3-A3, ISSN: 0959-9673

Conference paper

Rhys AD, Monteiro P, Smith C, Vaghela M, Arnandis T, Kato T, Leitinger B, Sahai E, McAinsh A, Charras G, Godinho SAet al., 2017, Loss of E-cadherin provides tolerance to centrosome amplification in epithelial cancer cells, Journal of Cell Biology, Vol: 217, Pages: 195-209, ISSN: 0021-9525

Centrosome amplification is a common feature of human tumors. To survive, cancer cells cluster extra centrosomes during mitosis, avoiding the detrimental effects of multipolar divisions. However, it is unclear whether clustering requires adaptation or is inherent to all cells. Here, we show that cells have varied abilities to cluster extra centrosomes. Epithelial cells are innately inefficient at clustering even in the presence of HSET/KIFC1, which is essential but not sufficient to promote clustering. The presence of E-cadherin decreases cortical contractility during mitosis through a signaling cascade leading to multipolar divisions, and its knockout promotes clustering and survival of cells with multiple centrosomes. Cortical contractility restricts centrosome movement at a minimal distance required for HSET/KIFC1 to exert its function, highlighting a biphasic model for centrosome clustering. In breast cancer cell lines, increased levels of centrosome amplification are accompanied by efficient clustering and loss of E-cadherin, indicating that this is an important adaptation mechanism to centrosome amplification in cancer.

Journal article

Gorlitz F, Corcoran DS, Garcia Castano EA, Leitinger B, Neil MAA, Dunsby CW, French PMWet al., 2017, Mapping molecular function to biological nanostructure: combining structured illumination microscopy with fluorescence lifetime imaging (SIM+FLIM), Photonics, Vol: 4, ISSN: 2304-6732

We present a new microscope integrating super-resolved imaging using structured illumination microscopy (SIM) with wide-field optically sectioned fluorescence lifetime imaging (FLIM) to provide optical mapping of molecular function and its correlation with biological nanostructure below the conventional diffraction limit. We illustrate this SIM + FLIM capability to map FRET readouts applied to the aggregation of discoidin domain receptor 1 (DDR1) in Cos 7 cells following ligand stimulation and to the compaction of DNA during the cell cycle.

Journal article

Juskaite V, Corcoran DS, Leitinger B, 2017, Collagen induces activation of DDR1 through lateral dimer association and phosphorylation between dimers., Elife, Vol: 6, Pages: 1-27, ISSN: 2050-084X

The collagen-binding receptor tyrosine kinase DDR1 (discoidin domain receptor 1) is a drug target for a wide range of human diseases, but the molecular mechanism of DDR1 activation is poorly defined. Here we co-expressed different types of signalling-incompetent DDR1 mutants ('receiver') with functional DDR1 ('donor') and demonstrate phosphorylation of receiver DDR1 by donor DDR1 in response to collagen. Making use of enforced covalent DDR1 dimerisation, which does not affect receptor function, we show that receiver dimers are phosphorylated in trans by the donor; this process requires the kinase activity of the donor but not that of the receiver. The receiver ectodomain is not required, but phosphorylation in trans is abolished by mutation of the transmembrane domain. Finally, we show that mutant DDR1 that cannot bind collagen is recruited into DDR1 signalling clusters. Our results support an activation mechanism whereby collagen induces lateral association of DDR1 dimers and phosphorylation between dimers.

Journal article

Woltersdorf C, Bonk M, Leitinger B, Huhtala M, Käpylä J, Heino J, Gil Girol C, Niland S, Eble JA, Bruckner P, Dreier R, Hansen Uet al., 2017, The binding capacity of α1β1-, α2β1- and α10β1-integrins depends on non-collagenous surface macromolecules rather than the collagens in cartilage fibrils., Matrix Biology, Vol: 63, Pages: 91-105, ISSN: 1569-1802

Interactions of cells with supramolecular aggregates of the extracellular matrix (ECM) are mediated, in part, by cell surface receptors of the integrin family. These are important molecular components of cell surface-suprastructures regulating cellular activities in general. A subfamily of β1-integrins with von Willebrand-factor A-like domains (I-domains) in their α-chains can bind to collagen molecules and, therefore, are considered as important cellular mechano-receptors. Here we show that chondrocytes strongly bind to cartilage collagens in the form of individual triple helical molecules but very weakly to fibrils formed by the same molecules. We also find that chondrocyte integrins α1β1-, α2β1- and α10β1-integrins and their I-domains have the same characteristics. Nevertheless we find integrin binding to mechanically generated cartilage fibril fragments, which also comprise peripheral non-collagenous material. We conclude that cell adhesion results from binding of integrin-containing adhesion suprastructures to the non-collagenous fibril periphery but not to the collagenous fibril cores. The biological importance of the well-investigated recognition of collagen molecules by integrins is unknown. Possible scenarios may include fibrillogenesis, fibril degradation and/or phagocytosis, recruitment of cells to remodeling sites, or molecular signaling across cytoplasmic membranes. In these circumstances, collagen molecules may lack a fibrillar organization. However, other processes requiring robust biomechanical functions, such as fibril organization in tissues, cell division, adhesion, or migration, do not involve direct integrin-collagen interactions.

Journal article

Barisione G, Fabbi M, Cutrona G, De Cecco L, Zupo S, Leitinger B, Gentile M, Manzoni M, Neri A, Morabito F, Ferrarini M, Ferrini Set al., 2017, Heterogeneous expression of the collagen receptor DDR1 in chronic lymphocytic leukaemia and correlation with progression, Blood Cancer Journal, Vol: 6, ISSN: 2044-5385

Journal article

Go¨rlitz F, Corcoran DS, Sparks H, Leitinger B, Neil M, Dunsby C, French Pet al., 2017, Mapping molecular function to biological nanostructure: Combining structured illumination microscopy with fluorescence lifetime imaging

We report the enhancement of spatial resolution and sensitivity of wide-field time-gated imaging and the combination with SIM to map molecular function using FRET to biological nanostructure below the conventional diffraction limit.

Conference paper

Borza CM, Su Y, Tran TL, Yu L, Steyns N, Temple KJ, Skwark MJ, Meiler J, Lindsley CW, Hicks BR, Leitinger B, Zent R, Pozzi Aet al., 2016, Discoidin domain receptor 1 kinase activity is required for regulating collagen IV synthesis, Matrix Biology, Vol: 57-58, Pages: 258-271, ISSN: 1569-1802

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds to and is activated by collagens. DDR1 expression increases following kidney injury and accumulating evidence suggests that it contributes to the progression of injury. To this end, deletion of DDR1 is beneficial in ameliorating kidney injury induced by angiotensin infusion, unilateral ureteral obstruction, or nephrotoxic nephritis. Most of the beneficial effects observed in the DDR1-null mice are attributed to reduced inflammatory cell infiltration to the site of injury, suggesting that DDR1 plays a pro-inflammatory effect. The goal of this study was to determine whether, in addition to its pro-inflammatory effect, DDR1 plays a deleterious effect in kidney injury by directly regulating extracellular matrix production. We show that DDR1-null mice have reduced deposition of glomerular collagens I and IV as well as decreased proteinuria following the partial renal ablation model of kidney injury. Using mesangial cells isolated from DDR1-null mice, we show that these cells produce significantly less collagen compared to DDR1-null cells reconstituted with wild type DDR1. Moreover, mutagenesis analysis revealed that mutations in the collagen binding site or in the kinase domain significantly reduce DDR1-mediated collagen production. Finally, we provide evidence that blocking DDR1 kinase activity with an ATP-competitive small molecule inhibitor reduces collagen production. In conclusion, our studies indicate that the kinase activity of DDR1 plays a key role in DDR1-induced collagen synthesis and suggest that blocking collagen-mediated DDR1 activation may be beneficial in fibrotic diseases.

Journal article

Leitinger B, 2016, Collagen sensing: how do discoidin domain receptors transmit a signal across the membrane?, 41st FEBS Congress on Molecular and Systems Biology for a Better Life, Publisher: Wiley, Pages: 49-49, ISSN: 1742-4658

Conference paper

Gao H, Chakraborty G, Zhang Z, Akalay I, Gadiya M, Gao Y, Sinha S, Hu J, Jiang C, Akram M, Brogi E, Leitinger B, Giancotti FGet al., 2016, Multi-organ site metastatic reactivation mediated by non-canonical discoidin domain receptor 1 signaling, Cell, Vol: 166, Pages: 47-62, ISSN: 0092-8674

Genetic screening identifies the atypical tetraspanin TM4SF1 as a strong mediator ofmetastatic reactivation of breast cancer. Intriguingly, TM4SF1 couples the collagenreceptor tyrosine kinase DDR1 to the cortical adaptor syntenin 2 and, hence, toPKC. The latter kinase phosphorylates and activates JAK2, leading to theactivation of STAT3. This non-canonical mechanism of signaling induces theexpression of SOX2 and NANOG, sustains the manifestation of cancer stem celltraits, and drives metastatic reactivation in the lung, bone, and brain. Bioinformaticanalyses and pathological studies corroborate the clinical relevance of thesefindings. We conclude that non-canonical DDR1 signaling enables breast cancercells to exploit the ubiquitous interstitial matrix component collagen I to undergometastatic reactivation in multiple target organs.

Journal article

Leitinger B, 2016, DDRs: Binding properties, cell adhesion and modulation of integrin function, Discoidin Domain Receptors in Health and Disease, Pages: 3-21, ISBN: 9781493963812

The discoidin domain receptors are a subfamily of receptor tyrosine kinases that consist of two members, DDR1 and DDR2. These closely related proteins are characterized by the presence of a discoidin homology (DS) domain in their extracellular regions, as well as a domain of similar structure, the DS-like domain. The DDRs function as transmembrane collagen receptors and are thus at the interface of receptor tyrosine kinases and integrins, the main receptors for extracellular matrix molecules. Both DDRs are activated by a number of different collagen types, with which they interact through a conserved ligand-binding trench that is contained in their DS domains. The DDRs have overlapping functions with integrins and can modulate cell adhesion and cell migration. Depending on the cellular context, DDR-induced signalling can impact integrin-mediated signalling in positive or negative ways. Here, the DDRs are discussed in terms of their molecular basis of collagen recognition, their roles in cell adhesion and migration and their ability to modulate integrin function.

Book chapter

An B, Abbonante V, Xu H, Gavriilidou D, Yoshizumi A, Bihan D, Farndale RW, Kaplan D, Balduini A, Leitinger B, Brodsky Bet al., 2015, Recombinant Collagen Engineered to Bind to Discoidin Domain Receptors Functions as a Receptor Inhibitor, Journal of Biological Chemistry, Vol: 291, Pages: 4343-4355, ISSN: 1083-351X

A bacterial collagen-like protein Scl2 has been developed as a recombinant collagen model system to host human collagen ligand binding sequences, with the goal of generating biomaterials with selective collagen bioactivities. Defined binding sites in human collagen for integrins, fibronectin, heparin, and MMP-1 have been introduced into the triple-helical domain of the bacterial collagen and led to the expected biological activities. The modular insertion of activities is extended here to the discoidin domain receptors (DDRs), which are collagen activated receptor tyrosine kinases. Insertion of the DDR binding sequence from human collagen III into bacterial collagen led to specific receptor binding. However, even at the highest testable concentrations, the construct was unable to stimulate DDR autophosphorylation. The recombinant collagen expressed in E. coli does not contain hydroxyproline (Hyp), and complementary synthetic peptide studies showed that replacement of Hyp by Pro at the critical Gly-Val-Met-Gly-Phe-Hyp position decreased the DDR binding affinity and consequently required a higher concentration for the induction of receptor activation. The ability of the recombinant bacterial collagen to bind the DDRs without inducing kinase activation suggested it could interfere with the interactions between animal collagen and the DDRs, and such an inhibitory role was confirmed in vitro and with a cell migration assay. This study illustrates that recombinant collagen can complement synthetic peptides in investigating structure-activity relationships, and this system has the potential for the introduction or inhibition of specific biological activities.

Journal article

Multhaupt HA, Leitinger B, Gullberg D, Couchman JRet al., 2015, Extracellular matrix component signaling in cancer., Advanced Drug Delivery Reviews, Vol: 97, Pages: 28-40, ISSN: 1872-8294

Cell responses to the extracellular matrix depend on specific signaling events. These are important from early development, through differentiation and tissue homeostasis, immune surveillance, and disease pathogenesis. Signaling not only regulates cell adhesion cytoskeletal organization and motility but also provides survival and proliferation cues. The major classes of cell surface receptors for matrix macromolecules are the integrins, discoidin domain receptors, and transmembrane proteoglycans such as syndecans and CD44. Cells respond not only to specific ligands, such as collagen, fibronectin, or basement membrane glycoproteins, but also in terms of matrix rigidity. This can regulate the release and subsequent biological activity of matrix-bound growth factors, for example, transforming growth factor-β. In the environment of tumors, there may be changes in cell populations and their receptor profiles as well as matrix constitution and protein cross-linking. Here we summarize roles of the three major matrix receptor types, with emphasis on how they function in tumor progression.

Journal article

Shitomi Y, Thogersen IB, Ito N, Leitinger B, Enghild JJ, Itoh Yet al., 2015, ADAM10 controls collagen signaling and cell migration on collagen by shedding the ectodomain of discoidin domain receptor 1 (DDR1), MOLECULAR BIOLOGY OF THE CELL, Vol: 26, Pages: 659-673, ISSN: 1059-1524

Journal article

Leitinger B, 2015, The DDR receptor family, Receptor Tyrosine Kinases: Family and Subfamilies, Pages: 79-106, ISBN: 9783319118871

The discoidin domain receptor subfamily consists of two members, the closely related DDR1 and DDR2 proteins, which are characterised by the presence of a discoidin homology (DS) domain in their extracellular regions. The DDRs are transmembrane collagen receptors, which places them at the interface between RTKs and receptors for the extracellular matrix. Both DDRs bind a number of different collagen types through a conserved ligand-binding trench that is contained in their DS domains. Collagen-induced receptor autophosphorylation is unusually slow and sustained, with the underlying mechanisms currently unknown. The DDRs form stable dimers in the absence of ligand, indicating that the paradigm of ligand-induced receptor dimerisation does not apply to the DDRs. Both DDRs are widely expressed in embryo development and in postnatal tissues and play important roles in development, with DDR1 required for mammary gland development and kidney function and DDR2 for the growth of long bones. Like many other RTKs, the DDRs regulate fundamental cellular functions, including cell proliferation and survival, adhesion and migration. In addition, they regulate tissue homeostasis by remodelling of extracellular matrices, through controlling matrix metalloproteinase expression and activity. Dysregulation of DDR function is associated with disease progression of a wide range of human diseases, including organ fibrosis, atherosclerosis, arthritis and many types of cancer, making the DDRs new promising therapeutic targets.

Book chapter

Di Martino J, Juin A, Leitinger B, Paysan L, Bomo J, Baffet G, Rosenbaum J, Moreau V, Saltel Fet al., 2014, Discoidin domain receptor 1 controls linear invadosome formation., ASCB/IFCB Meeting, Publisher: AMER SOC CELL BIOLOGY, ISSN: 1059-1524

Conference paper

Juin A, Di Martino J, Leitinger B, Henriet E, Gary A-S, Paysan L, Bomo J, Baffet G, Gauthier-Rouviere C, Rosenbaum J, Moreau V, Saltel Fet al., 2014, Discoidin domain receptor 1 controls linear invadosome formation via a Cdc42-Tuba pathway, The Journal of Cell Biology, Vol: 207, Pages: 517-533, ISSN: 0021-9525

Accumulation of type I collagen fibrils in tumors is associated with an increased risk of metastasis. Invadosomes are F-actin structures able to degrade the extracellular matrix. We previously found that collagen I fibrils induced the formation of peculiar linear invadosomes in an unexpected integrin-independent manner. Here, we show that Discoidin Domain Receptor 1 (DDR1), a collagen receptor overexpressed in cancer, colocalizes with linear invadosomes in tumor cells and is required for their formation and matrix degradation ability. Unexpectedly, DDR1 kinase activity is not required for invadosome formation or activity, nor is Src tyrosine kinase. We show that the RhoGTPase Cdc42 is activated on collagen in a DDR1-dependent manner. Cdc42 and its specific guanine nucleotide-exchange factor (GEF), Tuba, localize to linear invadosomes, and both are required for linear invadosome formation. Finally, DDR1 depletion blocked cell invasion in a collagen gel. Altogether, our data uncover an important role for DDR1, acting through Tuba and Cdc42, in proteolysis-based cell invasion in a collagen-rich environment.

Journal article

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