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Activation of Discoidin Domain Receptors by collagen VI and collagen I fibrils

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Title: Activation of Discoidin Domain Receptors by collagen VI and collagen I fibrils
Authors: Gavriilidou, Despoina
Item Type: Thesis or dissertation
Abstract: Discoidin domain receptors (DDRs) are members of the Receptor Tyrosine Kinase (RTK) family. There are two DDRs, DDR1 and DDR2. In embryo development, DDR1 function is vital for mammary gland development, whereas DDR2 is important in long bone growth. The DDRs also have key roles in several cellular functions, such as cell migration, adhesion, proliferation and matrix remodeling. The DDRs are unique RTK members due to the fact that they are activated by an extracellular matrix component, collagen. It is well known that the DDRs are activated by fibrillar collagens, such as collagen I, when present as single triple helices. However, it is less clear whether collagen I fibrils or fibers, the form in which collagen I is present in tissues, can act as functional DDR ligands and induce DDR phosphorylation. In this thesis, I show that DDR1 activation is induced by collagen I fibrils generated in vitro from different sources, and furthermore by extracellular matrix secreted from fibroblastic cells. I also show that DDR2 is activated to a much lower extent in comparison to DDR1. Another collagen type that is present in many tissues is collagen VI. Collagen VI has not been characterized as a DDR ligand. Collagen VI is secreted in the form of tetramers to extracellular matrices, where it associates to form microfibrils. In this thesis, I show that collagen VI tetramers and microfibrils bind strongly to both DDRs. However, they can induce only DDR1 phosphorylation, not DDR2 phosphorylation. Our preliminary data further suggest that the triple-helical region in collagen VI is the functional region that promotes DDR1 activation. Furthermore, I show that collagen VI binds to DDR2 by occupying another binding site than the fibrillar binding site. Finally, preliminary experiments suggest that collagen VI microfibrils can inhibit collagen I-induced DDR2 autophosphorylation. These data suggest that collagen VI binding to DDR2 could serve as a limiting factor for DDR2 activation in pathological conditions, such as osteoarthritis.
Content Version: Open Access
Issue Date: Apr-2017
Date Awarded: Aug-2017
URI: http://hdl.handle.net/10044/1/72245
DOI: https://doi.org/10.25560/72245
Copyright Statement: Creative Commons Attribution Non-Commercial No Derivatives licence
Supervisor: Leitinger, Birgit
Department: National Heart and Lung Institute
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:National Heart and Lung Institute PhD theses