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Role of Oligomerization in Discoidin Domain Receptors - Collagen Type I Interaction

Mihai, Cosmin
http://rave.ohiolink.edu/etdc/view?acc_num=osu1213203191

Abstract Details

2008, Doctor of Philosophy, Ohio State University, Biophysics.
Discoidin domain receptors (DDR1 and DDR2) are unique tyrosine kinase receptors (RTK) in that they bind to and are activated by collagens, including collagen type I. The mechanism(s) of DDRs binding to collagen is not completely understood. It is generally accepted that for receptors from the RTK family, ligand binding induces a transition from the monomeric to oligomeric state; however, the oligomeric state of DDRs and its modulation by collagens is not yet characterized. Using the purified DDR extracellular domain (ECD) we have been able to quantitatively describe its binding to collagen type I. We found that both DDR1 and DDR2 ECD require oligomerization for binding to collagen type I. At the same time we found that DDRs can clearly distinguish between the monomeric and fibrillar states of collagen with an increased affinity toward monomeric collagen. This can have significant physiological relevance, as the implication is that DDRs signaling is inhibited in the presence of mature collagen fibers. Using fluorescently labeled DDR1 and live cell imaging, we have found that collagen induces rapid aggregation and internalization of DDR1, followed by its incorporation in the early endosome. Fluorescence resonant energy transfer (FRET) experiments in live cells, confirmed that DDR1 exists as a dimer prior to collagen stimulation and that collagen-induced internalization applies preferentially to the dimeric fraction of the receptor population. The dynamics of receptor internalization suggest that DDR1 dimerization, collagen binding and receptor phosphorylation are independent events, separated both temporally and spatially. Further, in vitro work with purified DDR ECD, and live cell work with recombinant DNA, demonstrated a novel mechanism of collagen regulation by DDRs, namely that binding of DDRs to collagen can directly modulate collagen fibrillogenesis. Taken together, our studies improved our understanding of DDR-collagen interaction and generated new evidence that supports the role of DDR receptors as potent regulators of collagen deposition in the extracellular matrix.
Gunjan Agarwal, Dr./PhD (Advisor)
Terry Elton, Dr./PhD (Committee Member)
Anthony Brown, Dr./PhD (Committee Member)
144 p.
Biophysics
DDR; collagen; FRET; oligomerization; internalization; fibrillogenesis

Recommended Citations

Citations

  • Mihai, C. (2008). Role of Oligomerization in Discoidin Domain Receptors - Collagen Type I Interaction [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1213203191

    APA Style (7th edition)

  • Mihai, Cosmin. Role of Oligomerization in Discoidin Domain Receptors - Collagen Type I Interaction. 2008. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1213203191.

    MLA Style (8th edition)

  • Mihai, Cosmin. "Role of Oligomerization in Discoidin Domain Receptors - Collagen Type I Interaction." Doctoral dissertation, Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1213203191

    Chicago Manual of Style (17th edition)

osu1213203191
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© 2008, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.