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Molecular and Cellular Biology, November 2001, p. 7295-7306, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7295-7306.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Transformation of Chicken Embryo Fibroblasts by v-src Uncouples beta 1 Integrin-Mediated Outside-in but Not Inside-out Signaling

Anirban Datta,1,2 Qi Shi,1 and David E. Boettiger1,*

Department of Microbiology1 and Department of Biology,2 University of Pennsylvania, Philadelphia, Pennsylvania 19104

Received 29 January 2001/Returned for modification 8 March 2001/Accepted 23 July 2001

Adhesion of cells to extracellular matrix is mediated by integrin family receptors. The process of receptor-ligand binding is dependent on metabolic energy and is regulated by intracellular signals, termed inside-out signals. The strength of the initial alpha 5beta 1-mediated adhesion of v-src-transformed chicken embryo fibroblasts (v-srcCEF) was similar to that of normal CEF. A chemically cross-linked fibronectin substrate was able to restore cell spreading and the ability of v-srcCEF to assemble a fibronectin matrix. Over time, v-srcCEF showed decreased adhesion due to the reduction of alpha 5beta 1-fibronectin bonds consequent on the reduction of substrate-bound fibronectin due to the secretion of proteases by v-srcCEF. Excess synthesis of hyaluronic acid by v-srcCEF also reduced the alpha 5beta 1-fibronectin bonds and contributed to cell detachment at later times in culture. Thus, the adhesion defects were not due to a failure of alpha 5beta 1 function and adhesion of the v-srcCEF was alpha 5beta 1 dependent. Integrin-mediated adhesion also produces signals that affect cell proliferation and cell differentiation. An early consequence of these "outside-in" signals was the phosphorylation of FAK Y397 in direct proportion to the number of alpha 5beta 1-fibronectin bonds formed. In contrast, v-srcCEF had an increased level of phosphorylation on five different tyrosines in FAK, and none of these phosphorylation levels were sensitive to the number of alpha 5beta 1-fibronectin bonds. In the absence of serum, CEF proliferation was sensitive to changes in alpha 5beta 1-mediated adhesion levels. Transformation by v-src increased the serum-free proliferation rate and made it insensitive to alpha 5beta 1-mediated adhesion. Thus, the v-srcCEF were insensitive to the normal outside-in signals from alpha 5beta 1 integrin.

* Corresponding author. Mailing address: Department of Microbiology, University of Pennsylvania, 211 Johnson Pavilion, 36th & Hamilton Walk, Philadelphia, PA 19104. Phone: (215) 898-8792. Fax: (215) 898-9557. E-mail: boettige{at}mail.med.upenn.edu.

Molecular and Cellular Biology, November 2001, p. 7295-7306, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7295-7306.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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