The objective of this proposal is to examine the role of integrin in the process of Rous sarcoma virus induced cell transformation. Integrin is a cellular receptor for fibronectin and other extracellular matrix components and is one of the putative targets for the tyrosine kinase activity of pp60v-src. Site specific mutagenesis will be used to change the phosphorylated tyrosine and to modify the internal domain of the beta chain of integrin which includes the phosphorylated tyrosine. Vectors will be used to introduce normal and mutated beta subunit of chick integrin into Rous transformed cells, revertant cells and normal cells to access the effect of these mutants on the ability of pp60v-src to induce a transformed phenotype. The state of phosphorylation of integrin will be examined in cell membrane adhesion plaque fractions for the integrin mutants, cells transformed by different oncogenes, and during normal physiological processes. The interaction of integrin with the extracellular matrix will be manipulated by use of different substrates to determine the role of these linkages in the transformed phenotype.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA049866-03
Application #
3194180
Study Section
Virology Study Section (VR)
Project Start
1989-05-01
Project End
1994-04-30
Budget Start
1991-05-01
Budget End
1992-04-30
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Garcia, Andres J; Schwarzbauer, Jean E; Boettiger, David (2002) Distinct activation states of alpha5beta1 integrin show differential binding to RGD and synergy domains of fibronectin. Biochemistry 41:9063-9
Boettiger, D; Huber, F; Lynch, L et al. (2001) Activation of alpha(v)beta3-vitronectin binding is a multistage process in which increases in bond strength are dependent on Y747 and Y759 in the cytoplasmic domain of beta3. Mol Biol Cell 12:1227-37
Garcia, A J; Boettiger, D (1999) Integrin-fibronectin interactions at the cell-material interface: initial integrin binding and signaling. Biomaterials 20:2427-33
Garcia, A J; Vega, M D; Boettiger, D (1999) Modulation of cell proliferation and differentiation through substrate-dependent changes in fibronectin conformation. Mol Biol Cell 10:785-98
Garcia, A J; Huber, F; Boettiger, D (1998) Force required to break alpha5beta1 integrin-fibronectin bonds in intact adherent cells is sensitive to integrin activation state. J Biol Chem 273:10988-93
Shih, D T; Boettiger, D; Buck, C A (1997) Epitopes of adhesion-perturbing monoclonal antibodies map within a predicted alpha-helical domain of the integrin beta 1 subunit. J Cell Sci 110 ( Pt 20):2619-28
Boettiger, D; Enomoto-Iwamoto, M; Yoon, H Y et al. (1995) Regulation of integrin alpha 5 beta 1 affinity during myogenic differentiation. Dev Biol 169:261-72
Yoon, H; Boettiger, D (1994) Expression of v-src alters the expression of myogenic regulatory factor genes. Oncogene 9:801-7
Enomoto, M; Leboy, P S; Menko, A S et al. (1993) Beta 1 integrins mediate chondrocyte interaction with type I collagen, type II collagen, and fibronectin. Exp Cell Res 205:276-85
Enomoto, M I; Boettiger, D; Menko, A S (1993) Alpha 5 integrin is a critical component of adhesion plaques in myogenesis. Dev Biol 155:180-97

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