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2 edition of Exploring collagen interactions and activation modes of discoidin domain receptor 1. found in the catalog.

Exploring collagen interactions and activation modes of discoidin domain receptor 1.

Rahim Abdulhussein

Exploring collagen interactions and activation modes of discoidin domain receptor 1.

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Published .
Written in English


About the Edition

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase (RTK) activated by triple-helical collagens that has been implicated in a number of human diseases. Here, high affinity binding of the DDR1 extracellular domains to immobilized type I collagen is reported and the discoid in-collagen affinity quantified in vitro. Residues R105 & S175 and loop regions S52-T57 & R105-K112 in the collagen-binding discoidin domain of DDR1 were shown to be critically involved in collagen binding and receptor activation. Data presented here are the first to report that DDR1 exists as a ligand-independent disulfide-linked dimer. It was found that the stalk region, in particular cysteine residues 303 and 348, are critical to ligand interaction, dimerization and receptor activation. These data suggest DDR1 can form unconventional dimers not predicted by the current ligand-induced RTK dimerization model. This thesis provides new insights into the DDR1 collagen-signaling mechanism which may ultimately lead to the design of therapeutics that interfere with aberrant DDR1 function through disruption of receptor-ligand interaction, dimerization or receptor activation.

The Physical Object
Pagination98 leaves.
Number of Pages98
ID Numbers
Open LibraryOL19217179M
ISBN 100494073675

Construction of Recombinant Plasmids. Plasmid vectors for collagen-binding growth factors were prepared by modifying a plasmid, pCHC (), encoding a fusion protein between glutathione S-transferase (GST) and the collagen-binding domain (S2b + S3) of C. histolyticum collagenase.A rat EGF cDNA encoding a mature form (47 amino acids) was amplified by PCR from first-strand cDNAs .   Anti-glomerular basement membrane nephritis and Goodpasture syndrome result from autoantibody (Ab)-mediated destruction of kidney and lung. Ab target the noncollagenous 1 (NC1) domain of alpha3(IV) collagen, but little is known about Ab origins or structure. This ignorance is due in part to the inability to recover monoclonal Ab by transformation of patients’ blood cells. The aim of this Cited by: 4. The mission of the Vanderbilt University Medical Center's Center for Matrix Biology is to foster cohesive interactions among Vanderbilt University scientists who work, directly or indirectly, on extracellular matrix biology in order to facilitate collaborations, promote excellence and acquire funding support. 1)Synthesis (RER)-translation of collagen α-chains 2)Hydroxylation(ER)-requires VIT C 3)Glycosylation(ER)-form procollagen which is a triple helix of collagen α chains 4)Exocytosis of procollagen into extracellular space Outside Fibroblast: 5)Proteolytic cleavage --> becomes tropocollogen 6)Crosslinking --> becomes collagen fibrils.

FIG 1. The effect of L-ascorbic acid on collagen synthesis. Human skin fibroblasts at confluent density were exposed to L-ascorbic acid for a total of 72 hr. Fresh ascorbate was added each day. Cells were pulse labeled the final 6 hr with [2,3-IH1L-proline. The ' radioactivity incorporated into collagen and noncollagen protein was determined.


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Exploring collagen interactions and activation modes of discoidin domain receptor 1. by Rahim Abdulhussein Download PDF EPUB FB2

Introduction. The discoidin domain receptor (DDR) 2 family comprises two distinct members, DDR1 and DDR2, which were initially discovered in the early s and characterized as receptor tyrosine kinases (RTKs) based on the presence of a catalytic kinase domain (KD) (1–7).Subsequently, collagens were identified as ligands for DDRs (), thus establishing the unique Cited by: Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds and is activated by collagens.

Transcriptional profiling of cirrhosis in human liver using a DNA array and quantitative PCR detected elevated mRNA expression of DDR1 compared with that in nondiseased by: Interaction of Discoidin Domain Receptor 1 with Collagen type 1 Article (PDF Available) in Journal of Molecular Biology (2) April with Reads How we measure 'reads'.

The rate limiting step of phagocytosis is the binding of collagen to specific receptors, which include β1 integrins and the discoidin domain receptor 1 (DDR1). While these two receptors may interact, the functional nature of these interactions is not defined.

We examined the effects of DDR1 over-expression on β1 integrin function and Author: Lisa Alexandra Staudinger. Figure 1. Collagen activates MT1-MMP functions in RASF. A, human RASF were cultured on a plastic dish and stimulated with or without collagen I (Col-I; μg/ml) for 24 h in the presence or absence of GM (10 μ m), TIMP-1 ( n m), TIMP-2 ( n m), or DX ( n m).Media were analyzed by zymography for Exploring collagen interactions and activation modes of discoidin domain receptor 1.

book activation (Zymo), and cells were subjected to Western Cited by: Discoidin domain receptor 1 (DDR1) is a tyrosine kinase collagen adhesion receptor that mediates cell migration through association with non-muscle myosin IIA (NMIIA). Because DDR1 is implicated in cancer fibrosis, we hypothesized that DDR1 interacts with NMIIA to Cited by: Collagen Activation of Discoidin Domain Receptors.

A search for ligands of the DDR subfamily of receptor tyrosine kinases has revealed unexpectedly that collagen, one of the most abundant proteins in vertebrates, is able to bind and to activate both DDR by: Discoidin domain receptor 1 (DDR1) signaling in PC12 cells: Activation of juxtamembrane domains in PDGFR/DDR/TrkA chimeric receptors June The FASEB Journal 14(7)   Three different types of collagen-receptors are currently known: the tyrosine kinases discoidin domain receptor 1 and 2 (DDR1 and DDR2), 1 four integrin heterodimers containing the β1 subunit, and glycoprotein VI.

Although glycoprotein VI is only found on platelets, both integrins and DDR are widely expressed and trigger an array of signaling. Interactions between the discoidin domain receptor 1 and b1 integrin regulate attachment to collagen Lisa A.

Staudinger1, Stephen J. Spano1, Wilson Lee1, Nuno Coelho1, Dhaarmini Rajshankar1, Michelle P. Bendeck2, Tara Moriarty1 and Christopher A. McCulloch1,* 1Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, ON M5S 3E2, CanadaCited by: KIBRA interacts with discoidin domain receptor 1 to modulate collagen-induced signalling Heidi N.

Hilton a, Prudence M. Stanford a, Jessica Harris a,1, Samantha R. Oakes a, Warren Kaplan b, Roger J. Daly c, Christopher J. Ormandy a,⁎ a Development Group, Cancer Research Program, Garvan Institute of Medical Research, Sydney, NSW,Australia b Peter Wills Bioinformatics Centre, Garvan. Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a membrane-bound MMP that is highly expressed in cells with invading capacity, including fibroblasts and invasive cancer cells.

However, pathways of MT1-MMP up-regulation are not clearly understood. A potential physiological stimulus for MT1-MMP expression is fibrillar collagen, and it has been shown that it up-regulates both MT1-MMP Cited by: Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib.

Eur J Pharmacol44– Crossref, Medline, Google Scholar; DreuxAC, LambDJ, ModjtahediH, FernsGA (). The epidermal growth factor receptors and their family of ligands: their putative role in by: Inhibition of discoidin domain receptor 1 reduces collagen-mediated tumorigenicity in pancreatic ductal adenocarcinoma Kristina Y.

Aguilera, Huocong Huang, Wenting Du, Moriah M. Hagopian, Zhen Wang, Stefan Hinz, Tae Hyun Hwang, Huamin Wang, Jason B Fleming, Diego H. Castrillon, Xiaomei Ren, Ke Ding, Rolf A. BrekkenCited by: The IUPHAR/BPS Guide to Pharmacology. discoidin domain receptor tyrosine kinase 1 - Type XVI RTKs: DDR (collagen receptor) family.

Detailed annotation on the structure, function, physiology, pharmacology and clinical relevance of drug targets. Author Summary Collagens, the major extracellular matrix components in most vertebrate tissues, provide cells with structural and functional support.

Collagens are trimers of collagen α chains. Multiple trimers are formed by highly homologous α chains for certain types of collagens (e.g. α1α1α2, α3α4α5 and α5α5α6 heterotrimers for type IV collagen).

the activation of the tyrosine kinase Discoidin Domain Receptor 2 (DDR2) and the tyrosine phosphatase SHP DDR2 and SHP-2 were less activated in old collagen. DDR2 inhibition decreased SHP-2 phosphorylation in adult collagen and increased cell proliferation to a Cited by: 8. Discoidin domain receptors (DDRs), DDR1 and DDR2, are receptor tyrosine kinases (RTKs) with the unique ability among RTKs to respond to collagen.

DDRs have been reported to induce the expression of various pro-inflammatory and pro-fibrotic genes including matrix metalloproteinases (MMPs). We have previously shown that collagen I induces DDR1 and MMP through DDR2 activation and a janus Author: Pedro Ruiz, Gabor Jarai.

Recently, a novel receptor tyrosine kinase subfamily has been identified and designated as discoidin domain receptor tyrosine kinase type 1 (DDR1) and type 2 (DDR2). These are functional collagen receptors, whose tyrosine kinase is activated upon binding to : DT Boumpas, T Kuroiwa.

Several collagen-binding proteins (CBPs) are known to modulate collagen deposition and fibril diameter. However, limited studies exist on alterations in the fibril ultrastructure by CBPs. In this study, we elucidate how the collagen receptor, discoidin domain receptor 1 (DDR1) regulates the collagen content and ultrastructure in the adventitia.

The two discoidin domain receptors (DDRs), DDR1 and DDR2 are receptor tyrosine kinases (RTKs) with the unique ability among RTKs to respond to collagen.

We have previously shown that collagen I induces DDR1 and matrix metalloproteinase (MMP) expression through DDR2 activation and a Janus kinase (JAK)2 and extracellular signal-regulated kinase (ERK)1/2-mediated Cited by:   Ruiz PA, Jarai G: Collagen I induces discoidin domain receptor (DDR) 1 expression through DDR2 and a JAK2-ERK1/2-mediated mechanism in primary human lung fibroblasts.

J Biol Chem./jbc.M PubMedCentral CrossRef PubMed Google ScholarCited by: Collagen receptor integrins: evolution, ligand binding selectivity and the effect of activation Jyväskylä: University of Jyväskylä,67 p.

(Jyväskylä Studies in Biological and Environmental Science, ISSN ; ) ISBN (PDF), (nid.)File Size: KB. 3E3 reveals that the collagen-binding discoidin (DS) domain is tightly associated with the following DS-like domain, which contains the epitopes of all mAbs.

A conserved surface patch in the DS domain outside the collagen-binding site is shown to be required for signaling. Thus, the active conformation of the DDR1 dimer involves collagen-induced.

Significantly, knockdown of discoidin domain receptor 1 (DDR1), a collagen-binding protein that also co-localizes to cell-cell junctions, reversed the effects of Gα 13 knockdown on cell-cell adhesion and proteolytic invasion in three-dimensional by: 7. We show that activation of the collagen I receptor DDR2 (discoidin domain receptor 2) regulates SNAIL1 stability by stimulating ERK2 activity, in a Src-dependent manner.

Activated ERK2 directly phosphorylates SNAIL1, leading to SNAIL1 nuclear accumulation, reduced ubiquitylation and increased protein half-life.

RESEARCH Open Access Discoidin domain receptors regulate the migration of primary human lung fibroblasts through collagen matrices Pedro A Ruiz and Gabor Jarai* Abstract Background: The two discoidin domain receptors (DDRs), DDR1 and DDR2 are receptor tyrosine kinases (RTKs) with the unique ability among RTKs to respond to by:   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 Cited by: We recently identified the collagen I receptor discoidin domain receptor 2 (DDR2) as a novel upstream regulator of Snail1 protein stability.

Snail1 is a zinc finger transcriptional repressor that is considered to be a master regulator of the epithelial mesenchymal transition, which contributes to breast cancer metastasis by promoting tumor cell Author: Callie Corsa. Discoidin domain receptor (DDR) is a cell-surface receptor tyrosine kinase activated by the binding of its discoidin (DS) domain to fibrillar collagen.

Here, we have determined the NMR structure of the DS domain in DDR2 (DDR2-DS domain), and identified the binding site to fibrillar collagen by transferred cross-saturation by: In contrast, we demonstrate that the inhibition of the tyrosine-kinase collagen receptor discoidin domain receptor 2 (DDR2) has no impact on human primary neutrophil migration on 2D surfaces but is an important regulator of neutrophil chemotaxis in 3D collagen matrices.

Palo Alto, CA) with 1/6 vol of 7 concentrated DMEM, dilution to a final 1 DMEM solution, and incubation at 37°C for 24 hours Monomer collagen-coated dishes were prepared by incubating mg/ml of collagen so-lution in mol/L of acetic acid at 37°C for 24 hours and washing twice with DMEM before cell seeding.

Reagents and Antibodies. Abstract. We examined the possibility of whether angiotensin (Ang) II type 1 (AT 1) and type 2 (AT 2) receptor stimulation differentially regulates collagen production in mouse skin AT 1 and AT 2 receptors were expressed in neonatal skin fibroblasts prepared from wild-type mice to a similar degree, and the AT 1a receptor was exclusively expressed as opposed to the Cited by:   This video will cover the basics of the collagen types and the biochemical pathway of collagen synthesis.

(Effects and mechanisms of discoidin domain receptor 2 on type I collagen expression in cultured scleroderma dermal fibroblasts) ± fiE (ãákJl (systemic transforming growth factor 1 I & discoidin domain receptor 2 Y SSC DDR2 ä DDR2 1 SSC miRNA D Homo sapiens miR stemloop b DDR2 1 mRNA Y Y DDR2 TGF-PI small interfering RNA(siRNA) DDR2 D.

Structure Article Insights into Collagen Uptake by C-type Mannose Receptors from the Crystal Structure of Endo Domains 1–4 Patricia Paracuellos,1,2 David C. Briggs,1,2 Federico Carafoli,1 Tan Loncar,1 and Erhard Hohenester1,* 1Department of Life Sciences, Imperial College London, London SW7 2AZ, UK 2Co-first author *Correspondence: [email protected]   Steroid receptor coactivator-1 (SRC-1) plays a crucial role in nuclear receptor-mediated transcription including thyroid hormone receptor (TR)-dependent gene expression.

Interaction of the TR-ligand binding domain and SRC-1 through L XX LL motifs is required for this by: 5. activation of blood-vessel endothelium 1. IL-1 b. fever 2. IL-6 c. induction of IL-6 synthesis 3. CXCL8 d. increase in vascular permeability 4.

IL e. localized tissue destruction 5. TNF-f. production of acute-phase proteins by hepatocytes 6. type I interferons g. induction of resistance to viral replication h. activation of NK cells i.

The membrane surrounding each living cell contains a variety of proteins that carry out different roles. For example, proteins called receptor tyrosine kinases help a cell to receive signals from its external environment. Receptor tyrosine kinases span the membrane so that one part of the protein known as the ectodomain sticks out from the surface of the cell, while another part (called the Cited by: Type I collagen N‐Telopeptides adopt an ordered structure when docked to their helix receptor during fibrillogenesis**.

Background and Purpose. Adenosine A 2A receptor stimulation promotes the synthesis of collagen type I and type III (Col1 and Col3), mediators of fibrosis and scarring. The A 2A receptor modulates collagen balance via cAMP/PKA/p38‐MAPK/Akt pathways. Wnt signalling is important in fibrosis and the cAMP and Wnt pathways converge.

Because the A 2A receptor is Gs‐linked and increases cAMP, we Cited by: Buy Gating Nanodomains of the Acetylcholine Receptor: REFER analyses of 87 mutants in the M4 transmembrane segments indicate that the ¿M4 segment moves as single domain and in the middle of the gating reaction, with both ¿¿subunits moving synchronously.

Between the subunits, the sequence of M4 motions is ¿¿¿¿¿.Author: Ananya Mitra.The Cyc8–Tup1 complex inhibits transcription primarily by masking the activation domain of the recruiting protein Koon Ho Wong and Kevin Struhl1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston.