Disease relevance of MMRN1

• Recent studies identified multimerin as a specific coagulation factor V binding protein, complexed with platelet, but not plasma, factor V. These findings led us to investigate individuals with inherited factor V deficiencies for possible multimerin abnormalities [1].
• These data indicate that patients with factor V Quebec have an inherited bleeding disorder distinct from other platelet disorders and associated with multiple abnormalities, including multimerin deficiency, abnormal platelet factor V, thrombospondin, von Willebrand factor, and fibrinogen, and an epinephrine aggregation defect [1].
• The products of the collagen-alpha 1(I) and -alpha 2(I) genes form the triple helical molecule collagen type I, which constitutes the major ECM protein in tissue fibrosis [2].
• Degradation of ECM, particularly interstitial collagen, promotes plaque instability, rendering atheroma prone to rupture [3].
• Transgenic animals exhibiting nephritis as a result of treatment with anti--glomerular basement membrane antiserum showed significantly more persistent expansion of the mesangial ECM than was seen in parental mice [4].

Psychiatry related information on MMRN1

• Active MMP-2 may degrade A beta or act on ECM components critical in neuronal survival mechanisms and possibly play a role in Alzheimer's disease (AD) neuropathology [5].

High impact information on MMRN1

• Cadherin mediated cell compaction and cellular rearrangements may be analogous to integrin-mediated cell spreading and motility on the ECM [6].
• A hierarchy of ECM-mediated signalling regulates tissue-specific gene expression [7].
• The concept that the cytoskeleton and éxocellular matrix' (ECM) form an interactive scaffold for perception and transduction of positional information is relatively new [8].
• Cytokines secreted by cells that mediate the innate and adaptive immune responses play a critical role in regulating the synthesis of ECM components by fibroblasts [9].
• These findings underscore the potential importance of hepatic macrophages in regulating both stellate cell biology and ECM degradation during regression of hepatic fibrosis [10].

Chemical compound and disease context of MMRN1

• Taken together, our data indicate that PMA induces a rapid and temporary ECM-dependent enhancement of melanoma cell attachment and spreading, and that the response to ECM components appears not to be due to significant shifts in beta 1 integrin expression, but rather to activation of beta 1 integrins [11].
• Heparanase, a heparan sulfate-specific endo-beta-D-glucuronidase, plays an important role in tumor cell metastasis through the degradation of extracellular matrix heparan sulfate proteoglycans (ECM HSPG) [12].
• Human colon cancer cell lines LS174T and LiM6 were plated on plastic, on hepatocyte-derived ECM or on stromal ECM and in the presence of the antimetabolite 5-fluorouracil (5-FU). the topoisomerase I inhibitor camptothecin and the topoisomerase II inhibitor etoposide [13].
• This indicates that resveratrol may influence the two major factors in the ECM remodeling occurring with tumor invasion, suggesting it may have uses as a therapeutic agent for brain tumors [14].
• Two sugar analogs, 2-acetamido-2-deoxy-1,5-gluconolactone (CD80110) and 2-acetamido-1,5-imino-1,2,5-trideoxy-D-glucitol (CD 86022), were evaluated for their ability to inhibit 1) human ovarian carcinoma beta-NAG isoenzyme activities, 2) degradation of radiolabeled ECM mediated by HOC cells and beta-NAG, and 3) cell growth [15].

Biological context of MMRN1

• Ligand capture, cell adhesion, ELISA and flow cytometry analyses of platelet-MMRN1 binding, indicated that MMRN1 binds to integrins alphaIIbbeta3 and alphavbeta3 [16].
• Multimerin 1 (MMRN1) is a large, soluble, polymeric, factor V binding protein and member of the EMILIN protein family [16].
• Multimerin is a massive, disulfide-linked protein with a unique complementary DNA sequence [17].
• Analyses of point mutated constructs indicated that the multimerin 1 binding site in the C2 domain of factor V partially overlaps the phosphatidylserine binding site and that the factor V B domain enhances multimerin 1 binding [18].
• Multimerin has also been found in endothelial cells and has been cloned recently from an endothelial cell cDNA library [19].

Anatomical context of MMRN1

• Endothelial cell binding to MMRN1 was predominantly mediated by alphavbeta3 and did not require the MMRN1 RGD site or cellular activation [16].
• Expression studies, using a cell line capable of endothelial-like MMRN1 processing, indicated that MMRN1 adhesion to cellular receptors enhanced its extracellular matrix fiber assembly [16].
• Like many other alphavbeta3 ligands, MMRN1 had the ability to support adhesion of additional cell types, including stimulated neutrophils [16].
• In vivo, MMRN1 is found in platelets, megakaryocytes, endothelium and extracellular matrix fibers, but not in plasma [16].
• Multimerin is expressed by megakaryocytes and endothelial cells and stored within platelet alpha granules and endothelial cell Weibel-Palade bodies [17].

Associations of MMRN1 with chemical compounds

• Identification of the MMRN1 binding region within the C2 domain of human factor V [18].
• These studies implicate integrin-mediated binding in MMRN1 attachment to cells and indicate that MMRN1 is a ligand for alphaIIbbeta3 and alphavbeta3 [16].
• The complementary DNA sequence of multimerin indicates that multimerin is a novel protein, with Arg-Gly-Asp-Ser, coiled-coil, and epidermal growth factor-like domains [17].
• The ECM glycoprotein laminin has profound and varied actions on neurons in vitro [20].
• In the presence of the substrates hydrogen peroxide (H(2)O(2)) and NO(2)(-), cell and vessel wall-associated MPO catalyzed nitration of ECM protein tyrosine residues, with fibronectin identified as a major target protein [21].

Other interactions of MMRN1

• Recent studies have identified multimerin as a specific Factor V/Va binding protein that is complexed with Factor V within platelet alpha granules [17].
• Molecular analysis identified a genomic duplication of <0.9 Mb encompassing alpha-synuclein and multimerin 1 (SNCA-MMRN1), flanked by long interspersed repeat sequences (LINE L1) [22].
• Multimerin is a novel, massive, soluble protein that resembles von Willebrand factor in its repeating, homomultimeric structure [23].
• The gC1q modules are also found in a variety of noncomplement proteins, such as type VIII and X collagens, precerebellin, hibernation protein, multimerin, Acrp-30, and saccular collagen [24].
• EMILINs are characterized by a C-terminal gC1q globular domain, a short collagenous sequence, a long coiled-coil region and a new cysteine-rich N-terminal domain that can be considered a hallmark of the family being present also in multimerin [25].

Analytical, diagnostic and therapeutic context of MMRN1

• Light microscopic immunocytochemistry demonstrated multimerin in normal megakaryocytes and in Dami cells after stimulation with PMA [26].
• Both platelet and Dami cell multimerin demonstrated several subunit sizes on reduced SDS-PAGE [26].
• However, peptide mapping confirmed structural homology between the different multimerin subunits [26].
• We investigated the region in factor V important for multimerin 1 binding using modified enzyme-linked immunoassays and recombinant factor V constructs [18].
• Immunoprecipitation experiments confirmed that unusually large factor V was associated with multimerin and it remained associated in 0.5 M salt [27].

References