Faculty: Deane F. Mosher, MD
|Dept:||Professor, Biomolecular Chemistry|
|Contact:|| 4285B MSC
|Training Areas:||Molecular Pharmacology
MD/PhD (Scientist Training Program)
|Lab Website||Click Here|
Figure 1. Dissection of the Thrombospondin-1 (TSP1) type 1 repeats and their role in angiogenesis. TSP1 is a modular trimeric protein. A schematic of the individual modules present in each TSP1 monomer are shown (upper part of figure). The conserved amino acids of the three type 1 repeats (P123) are shown below the modules. The unique glycosylation and the disulfide bond pattern of the type 1 repeats are also noted. The roles for TSP1 and the recombinant type 1 repeats in endothelial cell migration and apoptosis are shown in the lower portion of the figure. This highlights the thesis work of Kristin Huwiler.
My laboratory studies how cells respond to various stimuli by changing shape and cell migration. The starting point is extracellular proteins such as fibronectin, vitronectin, and thrombospondins. These proteins are incorporated into the extracellular matrix and influence cellular behavior. The proteins are complex and multi-modular and have obscure structure/function relationships. All mediate cell adhesion and are recognized by cell surface integrins. All interact with a number of other molecules in the extracellular milieu. We use a variety of biochemical, biophysical, cell biological, molecular biological, immunochemical, histological, and ultrastructural techniques to analyze these these molecules and their functions.
Fibronectin assembles into extracellular matrix by binding reversibly to receptors on cell surfaces and then undergoing a conformational change or covalent crosslinking to be incorporated irreversibly into the extracellular matrix. The cytoskeleton controls fibronectin assembly by signalling pathways that are initiated by binding of two small lipid mediators, lysophosphatidic acid and sphingosine-1-phosphate, to receptors of the EDG family. The goal is to describe all parts of the fibronectin assembly pathway, from initial stimulation of EDG receptors to characterization of the cell surface molecules that respond to cell contraction by binding fibronectin. We are particularly interested in how integrin cell surface adhesion receptors participate in the assembly of fibronectin, how this participation is related to other functions of integrins, and the role of integrin phosphorylation in integrin function.
There are five described thrombospondin genes in vertebrates and one in flies. Single nucleotide polymorphisms (SNPs) of the genes for human thrombospondin-1, -2, and -4 have been linked to premature coronary artery disease. Mutations of thrombospondin-5 cause skeletal malformations. We are using recombinant baculoviruses to express multi-modular segments of thrombospondins and carry out pioneering studies that give insight into how the SNPs may cause pathophysiology. Our current goal is to understand the conserved and highly labile structure formed by the C-terminal 600 residues of thrombospondins. This portion of thrombospondin binds more than 20 Ca2+ ions with high cooperativity.
Our third project concerns how b1 and b7 integrins control the migration and survival of fibroblastic and hematopoietic cells. These studies are based on the finding that conserved tyrosines in the cytoplasmic domain of b1A mediate directed cell movement. The major focus of this project is how the integrins control the movement of eosinophils into tissues during allergic reactions.
Honors & Awards
- 1997 - R.F. Schilling WARF Professor
- 1982-87 - H.I. Rommes Fellow
- Johansson MW, Kruger SJ, Schiebler ML, Evans MD, Sorkness RL, Denlinger LC, Busse WW, Jarjour NN, Montgomery RR, Mosher DF, and Fain SB (2013). Markers of vascular perturbation correlate with airway structural change in asthma. Am J Respir Crit Care Med. 188:167-78. PMID: 23855693 [PubMed - in process]
- Moussavi-Harami SF, Annis DS, Ma W, Berry SM, Coughlin EE, Strotman LN, Maurer LM, Westphall MS, Coon JJ, Mosher DF, and Beebe DJ (2013). Characterization of Molecules Binding to the 70K N-Terminal Region of Fibronectin by IFAST Purification Coupled with Mass Spectrometry. J Proteome Res. 12:3393-404. Epub 2013 Jun 21. PMID: 23750785 [PubMed - in process]
- Johansson MW and Mosher DF (2013). Integrin activation States and eosinophil recruitment in asthma. Front Pharmacol. 4:33. Epub 2013 Apr 1. PMID: 23554594 [PubMed]
- Johansson MW, Gunderson KA, Kelly EA, Denlinger LC, Jarjour NN, and Mosher DF (2013). Anti-IL-5 attenuates activation and surface density of β(2) -integrins on circulating eosinophils after segmental antigen challenge. Clin Exp Allergy. 43:292-303. PMID: 23414537 [PubMed - in process]
- Johansson MW, Annis DS, and Mosher DF (2013). αMβ2 Integrin-Mediated Adhesion and Motility of Interleukin-5-Stimulated Eosinophils on Periostin. Am J Respir Cell Mol Biol. 48:503-510 [Epub ahead of print] PMID: 23306834
- Shelef MA, Bennin DA, Mosher DF, and Huttenlocher A (2012). Citrullination of fibronectin modulates synovial fibroblast behavior. Arthritis Res Ther. 14:R240. [Epub ahead of print] PMID: 23127210
- Tomasini-Johansson BR, Johnson IA, Hoffmann FM, and Mosher DF (2012). Quantitative microtiter fibronectin fibrillogenesis assay: use in high throughput screening for identification of inhibitor compounds. Matrix Biol. 31:360-7. Epub 2012 Aug 6. PMID: 22986508
- Hoffmann BR, Liu Y, and Mosher DF (2012). Modification of EGF-like module 1 of thrombospondin-1, an animal extracellular protein, by O-linked N-acetylglucosamine. PLoS One. 7:e32762. Epub 2012 Mar 5.PMID: 22403705
- Maurer LM, Annis DS, and Mosher DF (2012). IGD motifs, which are required for migration stimulatory activity of fibronectin type I modules, do not mediate binding in matrix assembly. PLoS One. 7:e30615. Epub 2012 Feb 15. PMID:22355321
- Maurer LM, Ma W, Eickstaedt NL, Johnson IA, Tomasini-Johansson BR, Annis DS, and Mosher DF (2012). Ligation of the fibrin-binding domain by β-strand addition is sufficient for expansion of soluble fibronectin. J Biol Chem. 287:13303-12. Epub 2012 Feb 20. PMID: 22351755
- Mosher DF and Adams JC (2012). Adhesion-modulating/matricellular ECM protein families: A structural, functional and evolutionary appraisal. Matrix Biol. PMID: 22265890
- Johansson MW, Han ST, Gunderson KA, Busse WW, Jarjour NN, and Mosher DF (2012). Platelet Activation, P-selectin, and Eosinophil ≤1-integrin Activation in Asthma. Am J Respir Crit Care Med. PMID: 22227382
- Hoffmann BR, Annis DS, and Mosher DF (2011). Reactivity of the N-terminal region of fibronectin protein to transglutaminase 2 and factor XIIIA. J Biol Chem. 286:32220-30. PMID: 21757696
- Johansson MW and Mosher DF (2011). Activation of beta1 integrins on blood eosinophils by P-selectin. Am J Respir Cell Mol Biol. 45:889-97. PMID: 21441381
- Maurer LM, Tomasini-Johansson BR, Ma W, Annis DS, Eickstaedt NL, Ensenberger MG, Satyshur KA, and Mosher DF (2010). Extended binding site on fibronectin for the functional upstream domain of protein F1 of Streptococcus pyogenes. J Biol Chem. 285:41087-99. PMID: 20947497
- Xu J, Maurer LM, Hoffmann BR, Annis DS, and Mosher DF (2010). iso-DGR sequences do not mediate binding of fibronectin N-terminal modules to adherent fibronectin-null fibroblasts. J Biol Chem. 285:8563-71. PMID: 20097751