Deane Mosher, MD

Portrait of Deane Mosher, MD
Professor
Biomolecular Chemistry
Address: 
4285 MSC
1300 University Ave
Madison, WI 53706
Telephone: 
(608) 262-1576
Focus Groups: 
Cancer Biology
Signal Transduction
Education: 
MD, Harvard Medical School
Research Summary: 
Extracellular matrix; cell adhesion
Research Detail: 

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.

Selected Publications: 
Sabatier L, Chen D, Fagotto-Kaufmann C, Hubmacher D, McKee MD, Annis DS, Mosher DF, Reinhardt DP. Fibrillin assembly requires fibronectin. Mol Biol Cell 20:846-58, 2009.
Liu A, Mosher DF, Murphy-Ullrich JE, Goldblum SE. The counteradhesive proteins, thrombospondin 1 and SPARC/osteonectin, open the tyrosine phosphorylation-responsive paracellular pathway in pulmonary vascular endothelia. Microvasc Res 77:13-20, 2009.
Xu J, Bae E, Zhang Q, Annis DS, Erickson HP, Mosher DF. Display of cell surface sites for fibronectin assembly is modulated by cell adherence to 1F3 and C-terminal modules of fibronectin. PLoS ONE 4:e4113, 2009.
Liu A, Garg P, Yang S, Gong P, Pallero MA, Annis DS, Liu Y, Passaniti, A, Mann D, Mosher DF, Murphy-Ullrich J, Goldblum SE. The EGF-like repeats of thrombospondins activate phospholipase C-γ and increase epithelial cell migration through indirect epidermal growth factor receptor activation. J Biol Chem 284:6389-402, 2009.
Zhou X, Rowe RG, Hiraoka N, George JP, Wirtz D, Mosher DF, Virtanen I, Chernousov MA, Weiss SJ. Fibronectin fibrillogenesis regulates 3-dimensional neovessel formation. Genes Devel 22:1231-43, 2008.
Johansson MW, Kelly EAB, Busse WW, Jarjour NN, Mosher DF. Upregulation and activation of eosinophil integrins in blood and airway after segmental lung antigen challenge. J Immunol 180: 7622-35, 2008.
Carlson CB, Liu Y, Keck JL, Mosher DF. Influences of the Asn700Ser thrombosponin-1 polymorphism on protein structure and stability. J Biol Chem 283:20069-76, 2008.
Pallero MA, Elzie CA, Chen J, Mosher DF, Murphy-Ullrich JE. Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis. FASEB J 22:3968-79, 2008.
Carlson CB, Gunderson KA, Mosher DF. Mutations targeting intermodular interfaces or calcium binding destabilize the thrombospondin-2 signature domain. J Biol Chem 283:27089-99, 2008.
Isenberg JS, Annis DS, Pendrak ML, Ptaszynska M, Frazier WA, Mosher DF, Roberts DD. Differential interactions of thrombospondins-1, -2, and -4 with CD47 and effects on cGMP signaling and ischemic injury responses. J Biol Chem 284:1116-25, 2009.