Discoidin Domain Receptors in Health and Disease by Rafael Fridman, Paul H. Huang

By Rafael Fridman, Paul H. Huang

The interactions of cells with their surrounding extracellular matrix (ECM) performs a pivotal position in riding basic mobile habit, from improvement to tissue differentiation and serve as. on the mobile point, organ homeostasis will depend on a efficient conversation among cells and ECM, which ultimately ends up in the traditional phenotypic repertoire that signify each one telephone variety within the organism. A failure to set up those basic interactions and to interpret the cues emanating from the ECM is among the significant factors in irregular improvement and the pathogenesis of a number of illnesses. to acknowledge and act upon the biophysical signs which are generated through the pass speak among cells and ECM, the cells constructed particular receptors, between them a different set of receptor tyrosine kinases (RTKs), referred to as the Discoidin area Receptors (DDRs). The DDRs are the single RTKs that particularly bind to and are activated by way of collagen, an incredible protein section of the ECM. consequently, the DDRs are a part of the signaling networks that translate info from the ECM, and therefore they're key regulators of cell-matrix interactions. lower than physiological stipulations, DDRs keep watch over mobilephone and tissue homeostasis by means of performing on collagen sensors; transducing indications that keep an eye on phone polarity, tissue morphogenesis, phone differentiation, and collagen deposition. DDRs play a key function in ailments which are characterised via disorder of the stromal part, which result in irregular collagen deposition and the ensuing fibrotic reaction that disrupt general organ functionality in ailment of the cardiovascular procedure, lungs and kidneys, simply to point out a couple of. In melanoma, DDRs are hijacked by way of tumor and stromal cells to disrupt basic cell-collagen communique and begin pro-oncogenic courses. Importantly, a number of melanoma forms convey DDR mutations, that are idea to change receptor functionality, and give a contribution to melanoma development. for this reason, the powerful causative organization among altered RTK functionality and affliction it's been translated this day within the improvement of particular tyrosine kinase inhibitors focusing on DDRs for numerous sickness stipulations. even with the gathering facts highlighting the significance of DDRs in well-being and illnesses, there's nonetheless a lot to profit approximately those designated RTKs, as of at the present time there's a lack within the clinical literature of a publication committed completely to DDRs. this is often the 1st complete quantity devoted to DDRs, with a purpose to fill a spot within the box and serve these attracted to the medical neighborhood to profit extra approximately those very important receptors in wellbeing and fitness and disease.

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Protein Sci 7(7):1626–1631 40. Kiedzierska A, Smietana K, Czepczynska H, Otlewski J (2007) Structural similarities and functional diversity of eukaryotic discoidin-like domains. Biochim Biophys Acta 1774(9):1069–1078. 007 41. Abdulhussein R, McFadden C, Fuentes-Prior P, Vogel WF (2004) Exploring the collagenbinding site of the DDR1 tyrosine kinase receptor. J Biol Chem 279(30):31462–31470 42. Bargal R, Cormier-Daire V, Ben-Neriah Z, Le Merrer M, Sosna J, Melki J, Zangen DH, Smithson SF, Borochowitz Z, Belostotsky R, Raas-Rothschild A (2009) Mutations in DDR2 gene cause SMED with short limbs and abnormal calcifications.

Since collagen-independent functions of the DDRs have been described [3], it is possible that other receptors, including other RTKs, can induce DDR activation. Alternatively, as yet undefined, non-collagenous DDR ligands may be responsible for collagen-independent DDR functions. 1 DDRs: Binding Properties, Cell Adhesion and Modulation of Integrin Function 17 References 1. Shrivastava A, Radziejewski C, Campbell E, Kovac L, McGlynn M, Ryan TE, Davis S, Goldfarb MP, Glass DJ, Lemke G, Yancopoulos GD (1997) An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors.

2 Location of DDR2 binding sites on tropocollagen I and their functional significance Binding site DDR21 Toolkit peptide III-5 Distance from N-telo 18–26 nm DDR22 II-13 62–70 nm DDR23 DDR1 II-22/ II-23 113–116 nm DDR24 DDR25 III-39 II-44/ III-44 – 222–227 nm Sequence on col1 α-chains Amino acid location: 64–90 α1(I): GERGPPGPQGARGLP GTAGLPGMKGHR α2(I): GERGVVGPQGARGF PGTPGLPGFKGIRG Amino acid location: 217–243 α1(I): GAKGANGAPGIAG APGFPGARGPSGPQ α2(I): GAKGAAGLPGVAG APGLPGPRGIPGPP Amino acid location: 394–405 α1(I): GPPGARGQAGVMGFPGPK α2(I): GPVGARGEPGNIGFPGPK Not conserved Amino acid location: 775–792 α1(I): GIAGQRGVVGLPGQRGER GFPGLPGPS α2(I): GLLGAPGILGLPGSRG ERGLPGVAGAV Significance Cross-linking and glycosylation at K87; fibromodulin binding Collagen glycosylation at K219; KSPG region on microfibril Binding site for SPARC, vWF; DSPG region on microfibril – Collagenase cleavage site; MMP1 binding; fibrillogenesis inhibition; fibromodulin binding; KSPG region The five DDR2 binding sites as determined using toolkit peptides are numbered as DDR21 to DDR25 in the order in which they occur from the N to C terminus of tropocollagen I.

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