The extracellular matrix (ECM) provides cues to cells and thus serves as a framework for cell proliferation, migration, adhesion, and differentiation. Cell responses to changes in matrix composition and structure are interpreted through interactions with integrins and other receptors for matrix proteins. Cytoskeletal reorganization, changes in cell morphology, activation of signal transduction cascades, modulation of gene expression patterns, and progression through the cell cycle represent some of the cellular responses to matrix signals. The overall goal of this new proposal is to provide insights into the control of cell phenotype by ECM interactions with integrin receptors. Fibronectin (FN), an essential ECM component, interacts with cells from within a 3-dimensional fibrillar matrix. The structure of FN matrix fibrils can be varied by cell assembly of different recombinant native and mutant FNs. The principal investigator has found that structurally distinct FN matrices have different effects on cell growth rates and activation of focal adhesion kinase. These differential effects are ablated by inhibition of FN fibril formation. The mechanisms by which matrix FN modulates cell function will be investigated using cell culture systems combined with microscopic, biochemical, and molecular approaches.
Aim 1 is to analyze the role of focal adhesion components, cell shape, and other cell surface receptors in the growth response to FN matrix structure.
Aim 2 is to examine the contributions of downstream signaling pathways involving MAP kinase and PI3-kinase to cell growth and regulation of FN assembly. Integrin cytoplasmic domains are essential for the transmission of signals from the matrix through integrins to intracellular compartments. To dissect cytoplasmic domain function, the PI has developed an in vivo, Caenorhabditis elegans model system. Dominant negative phenotypes are generated in transgenic nematodes expressing chimeric proteins containing integrin b tails.
Aim 3 is to characterize the phenotypes caused by intact and mutant b tails in such transgenic nematodes.
Aim 4 is to to screen mutant transgenic nematode lines and thus identify genes that particpate in integrin function.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059383-04
Application #
6520025
Study Section
Special Emphasis Panel (ZRG1-MEDB (01))
Program Officer
Flicker, Paula F
Project Start
1999-06-01
Project End
2003-07-06
Budget Start
2002-06-01
Budget End
2003-07-06
Support Year
4
Fiscal Year
2002
Total Cost
$283,782
Indirect Cost
Name
Princeton University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Meighan, Christopher M; Schwarzbauer, Jean E (2014) ? Integrin cytoplasmic tails have tissue-specific roles during C. elegans development. Int J Dev Biol 58:325-33
Park, J; Schwarzbauer, J E (2014) Mammary epithelial cell interactions with fibronectin stimulate epithelial-mesenchymal transition. Oncogene 33:1649-57
Wong, Ming-Ching; Kennedy, William P; Schwarzbauer, Jean E (2014) Transcriptionally regulated cell adhesion network dictates distal tip cell directionality. Dev Dyn 243:999-1010
Carraher, Cara L; Schwarzbauer, Jean E (2013) Regulation of matrix assembly through rigidity-dependent fibronectin conformational changes. J Biol Chem 288:14805-14
Donnelly, Patrick E; Jones, Casey M; Bandini, Stephen B et al. (2013) A Simple Nanoscale Interface Directs Alignment of a Confluent Cell Layer on Oxide and Polymer Surfaces. J Mater Chem B 1:3553-3561
Wong, Ming-Ching; Schwarzbauer, Jean E (2012) Gonad morphogenesis and distal tip cell migration in the Caenorhabditis elegans hermaphrodite. Wiley Interdiscip Rev Dev Biol 1:519-31
Martynovsky, Maria; Wong, Ming-Ching; Byrd, Dana T et al. (2012) mig-38, a novel gene that regulates distal tip cell turning during gonadogenesis in C. elegans hermaphrodites. Dev Biol 368:404-14
Chiang, Chunyi; Karuri, Stella W; Kshatriya, Pradnya P et al. (2012) Surface derivatization strategy for combinatorial analysis of cell response to mixtures of protein domains. Langmuir 28:548-56
Hunt, Geoffrey C; Singh, Purva; Schwarzbauer, Jean E (2012) Endogenous production of fibronectin is required for self-renewal of cultured mouse embryonic stem cells. Exp Cell Res 318:1820-31
Singh, Purva; Schwarzbauer, Jean E (2012) Fibronectin and stem cell differentiation - lessons from chondrogenesis. J Cell Sci 125:3703-12

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