Faculty & Research
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Molecular Biology Faculty

Jean E. Schwarzbauer

Professor of Molecular Biology
associate chair, molecular biology

Jean E. Schwarzbauer

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Phone (609) 258-2893
locationSchultz Lab, 315
Phone Lab (609) 258-2915


Faculty Assistant
Matt Montondo
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Phone (609) 258-2664

 

Research Focus

Extracellular matrix regulation of cell functions

The extracellular matrix is essential for normal organization and function of all tissues. The matrix network is assembled by cells from secreted glycoproteins and proteoglycans which provide specific environmental signals to control cell morphology, migration, differentiation, and proliferation. Deficiencies in matrix composition and architecture correspond with the onset and progression of major diseases including cancer, atherosclerosis, and arthritis. The overall goal of our research is to determine how tissue-specific variations in matrix structure and organization regulate and modulate cell activities.

One of the major components of extracellular matrix is fibronectin, a large, adhesive glycoprotein. Fibronectin interacts with cells and transmits signals primarily through integrin receptors. Integrins constitute a large family of heterodimeric receptors with specificity for extracellular matrix and cell surface ligands. Multiple integrins can recognize fibronectin and, in so doing, activate cell adhesion, migration, and proliferation. We have developed cell culture-based systems to dissect the morphological and intracellular consequences of cell interactions with different types of fibronectin matrix. Comparison of assembly of normal and mutant recombinant proteins shows that fibronectin dimers are formed into multimeric complexes by binding to integrins at the cell surface which in turn stimulates fibril formation through binding to other fibronectin molecules. Mutant fibronectins that form structurally distinct fibril organizations have dramatic effects on cells such as delayed cytoskeletal reorganization and slowed cell cycle progression. Therefore, differences in fibronectin matrix can cause profound changes in intracellular functions and can modulate cell growth.

Fibronectin is also crucial in wound repair where it is first assembled along with fibrin into the blood clot provisional matrix that forms at sites of injury. We are using a synthetic fibronectin-fibrin clot matrix as a three-dimensional substrate for analyses of matrix control of cell behavior. Cells interacting with this matrix have a unique morphology with many lamellipodia indicating a motile phenotype. The provisional matrix in vivo contacts many other matrix proteins in the tissue around the wound. Incorporation of one of these proteins tenascin into the fibronectin-fibrin matrix induces a dramatic change to an elongated cell morphology with numerous actin-rich filopodia. Analyses of the signals induced by changes in the provisional matrix show that activation of the small GTPase RhoA is suppressed by tenascin. Thus, the cytoskeletal and cell shape changes result from differential regulation of members of the Rho GTPase family by distinct extracellular matrix components. This novel mechanism allows relatively modest changes in matrix composition to have major effects on cell responses.

Integrin receptors for extracellular matrix are highly conserved in all multicellular organisms and are the key to transmission of matrix information. We have generated transgenic nematodes that over-express a protein composed of the transmembrane and cytoplasmic domains of the Caenorhabditis elegans beta integrin subunit encoded by the pat-3 gene. These animals show dominant negative phenotypes consistent with disruption of endogenous integrin function such as defective muscle filament organization, movement defects, body deformities and infertility. Mutations in known binding sites within the beta(pat-3) cytoplasmic domain modulate the severity of these phenotypes. Transgenic nematodes with specific cytoplasmic domain mutations are now being developed for genetic screens to identify genes involved in intracellular signaling initiated via integrin engagement by extracellular matrix.


Selected Publications

Miller CG, Pozzi A, Zent R, Schwarzbauer JE. (2014) Effects of high glucose on integrin activity and fibronectin matrix assembly by mesangial cells. Mol Biol Cell. Jun 18. [Epub ahead of print]

Wong MC, Kennedy WP, Schwarzbauer JE. (2014) Transcriptionally regulated cell adhesion network dictates distal tip cell directionality. Dev Dyn. 243: 999-1010. Pubmed

Singh S, Bandini SB, Donnelly PE, Schwartz J, Schwarzbauer JE. (2014) A cell-assembled, spatially aligned extracellular matrix to promote directed tissue development. J Mater Chem B Mater Biol Med. 2: 1449-53. Pubmed

Desai VD, Hsia HC, Schwarzbauer JE. (2014) Reversible modulation of myofibroblast differentiation in adipose-derived mesenchymal stem cells. PLoS One. 9:e86865. Pubmed

Donnelly PE, Jones CM, Bandini SB, Singh S, Schwartz J, Schwarzbauer JE. (2013) A simple nanoscale interface directs alignment of a confluent cell layer on oxide and polymer surfaces. J Mater Chem B Mater Biol Med. 1: 3553-61. Pubmed

Park J, Schwarzbauer JE. (2013) Mammary epithelial cell interactions with fibronectin stimulate epithelial-mesenchymal transition. Oncogene. 33: 1649-57. Pubmed

Carraher CL, Schwarzbauer JE. (2013) Regulation of matrix assembly through rigidity-dependent fibronectin conformational changes. J Biol Chem. 288: 14805-14 Pubmed

Wong MC, Schwarzbauer JE. (2013) Gonad morphogenesis and distal tip cell migration in the Caenorhabditis elegans hermaphrodite. Wiley Interdiscip Rev Dev Biol. 1: 519-31. Pubmed

Singh P, Schwarzbauer JE. (2012) Fibronectin and stem cell differentiation - lessons from chondrogenesis. J Cell Sci. 125: 3703-12. Pubmed

Martynovsky M, Wong MC, Byrd DT, Kimble J, Schwarzbauer JE. (2012) mig-38, a novel gene that regulates distal tip cell turning during gonadogenesis in C. elegans hermaphrodites. Dev Biol. 368: 404-14 Pubmed

Hunt GC, Singh P, Schwarzbauer JE. (2012) Endogenous production of fibronectin is required for self-renewal of cultured mouse embryonic stem cells. Exp Cell Res. 318: 1820-31. PubMed

Wong MC, Martynovsky M, Schwarzbauer JE. (2011) Analysis of cell migration using Caenorhabditis elegans as a model system. Methods Mol Biol. 769: 233-47. PubMed

Schwarzbauer JE, Desimone DW. (2011) Fibronectins, their fibrillogenesis, and in vivo functions. Cold Spring Harb Perspect Biol. 3. pii: a005041. PubMed

Singh P, Carraher C, Schwarzbauer JE. (2010) Assembly of fibronectin extracellular matrix. Annu Rev Cell Dev Biol. 26: 397-419. PubMed

Engler AJ, Chan M, Boettiger D, Schwarzbauer JE. (2009) A novel mode of cell detachment from fibrillar fibronectin matrix under shear. J Cell Sci. 122: 1647-53. PubMed

Quinn JA, Graeber CT, Frackelton AR Jr, Kim M, Schwarzbauer JE, Filardo EJ. (2009) Coordinate regulation of estrogen-mediated fibronectin matrix assembly and epidermal growth factor receptor transactivation by the G-protein-coupled receptor, GPR30. Mol Endocrinol. 23: 1052-64. PubMed

Karuri NW, Lin Z, Rye HS, Schwarzbauer JE. (2009) Probing the conformation of the fibronectin III1-2 domain by fluorescence resonance energy transfer. J Biol Chem. 284: 3445-52. PubMed

Hunt GC, Schwarzbauer JE. (2009) Tightening the connections between cadherins and fibronectin matrix. Dev Cell. 16: 327-28. PubMed

Meighan CM, Schwarzbauer JE. (2008) Temporal and spatial regulation of integrins during development. Curr Opin Cell Biol. 20: 520-24. PubMed

Williams CM, Engler AJ, Slone RD, Galante LL, Schwarzbauer JE. (2008) Fibronectin expression modulates mammary epithelial cell proliferation during acinar differentiation. Cancer Res. 68: 3185-92. PubMed

Engler AJ, Sweeney HL, Discher DE, Schwarzbauer JE. (2007) Extracellular matrix elasticity directs stem cell differentiation. J Musculoskelet Neuronal Interact. 7: 335. PubMed

Galante LL, Schwarzbauer JE. (2007) Requirements for sulfate transport and the diastrophic dysplasia sulfate transporter in fibronectin matrix assembly. J Cell Biol. 179: 999-1009. PubMed

Meighan CM and Schwarzbauer JE. (2007) Control of C. elegans hermaphrodite gonad size and shape by vab-3/Pax6-mediated regulation of integrin receptors. Genes Dev. 21: 1615-20. PubMed

Valenick LV, Schwarzbauer JE. (2007) Ligand density and integrin repertoire regulate cellular response to LPA. Matrix Biol. 25: 223-31. PubMed

Dennes TJ, Hunt GC, Schwarzbauer JE, Schwartz J. (2007) High-yield activation of scaffold polymer surfaces to attach cell adhesion molecules. J Am Chem Soc. 129: 93-97. PubMed

Cram EJ, Shang H, Schwarzbauer JE. (2006) A systematic RNA interference screen reveals a cell migration gene network in C. elegans. J Cell Sci. 119: 4811-18. PubMed

Wierzbicka-Patynowski I, Mao Y, Schwarzbauer JE. (2007) Continuous requirement for pp60-Src and phospho-paxillin during fibronectin matrix assembly by transformed cells. J Cell Physiol. 210: 750-56. PubMed

Mao Y, Schwarzbauer JE. (2006) Accessibility to the fibronectin synergy site in a 3D matrix regulates engagement of alpha5beta1 versus alphavbeta3 integrin receptors. Cell Commun Adhes. 13: 267-77. PubMed

Valenick LV, Hsia HC, Schwarzbauer JE. (2005) Fibronectin fragmentation promotes alpha4beta1 integrin-mediated contraction of a fibrin-fibronectin provisional matrix. Exp Cell Res. 309: 48-55. PubMed

Lee M, Shen B, Schwarzbauer JE, Ahn J, Kwon J. (2005) Connections between integrins and Rac GTPase pathways control gonad formation and function in C. elegans. Biochim Biophys Acta. 1723: 248-55. PubMed

Midwood KS, Valenick LV, Hsia HC, Schwarzbauer JE. (2004) Coregulation of fibronectin signaling and matrix contraction by tenascin-C and syndecan-4. Mol Biol Cell. 15: 5670-77. PubMed

Midwood KS, Carolus MD, Danahy MP, Schwarzbauer JE, Schwartz J. (2004) Easy and efficient bonding of biomolecules to an oxide surface of silicon. Langmuir. 20: 5501-05. PubMed

Cram EJ, Schwarzbauer JE. (2004) The talin wags the dog: new insights into integrin activation. Trends Cell Biol. 14: 55-57. PubMed

Wierzbicka-Patynowski I, Schwarzbauer JE. (2003) The ins and outs of fibronectin matrix assembly. J Cell Sci. 116: 3269-76. PubMed

Cram EJ, Clark SG, Schwarzbauer JE. (2003) Talin loss-of-function uncovers roles in cell contractility and migration in C. elegans. J Cell Sci. 116: 3871-78. PubMed

Wierzbicka-Patynowski I, Schwarzbauer JE .(2002) Regulatory role for SRC and phosphatidylinositol 3-kinase in initiation of fibronectin matrix assembly. J Biol Chem. 277: 19703-08. PubMed

Sechler JL, Rao H, Cumiskey AM,...Schwarzbauer JE. (2001) A novel fibronectin binding site required for fibronectin fibril growth during matrix assembly. J Cell Biol. 154: 1081-88. PubMed

Lee M, Cram EJ, Shen B, Schwarzbauer JE. (2001) Roles for beta(pat-3) integrins in development and function of Caenorhabditis elegans muscles and gonads. J Biol Chem. 276: 36404-10. PubMed

Wenk MB, Midwood KS and Schwarzbauer JE (2000). Tenascin-C suppresses Rho activation. J Cell Biol 150: 913-920. PubMed

Brenner KA, Corbett SA and Schwarzbauer JE (2000). Regulation of fibronectin matrix assembly by activated Ras in transformed cells. Oncogene 19: 3156-3163 PubMed

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