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Molecular and Cellular Biology, February 2001, p. 902-915, Vol. 21, No. 3
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.3.902-915.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Gas6 Induces Growth, beta -Catenin Stabilization, and T-Cell Factor Transcriptional Activation in Contact-Inhibited C57 Mammary Cells

Sandro Goruppi,1,dagger Cristina Chiaruttini,1 Maria Elisabetta Ruaro,1 Brian Varnum,2 and Claudio Schneider1,3,*

LNCIB (Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie), 34012 Trieste,1 and Dipartimento di Scienze e Tecnologie Biomediche, Universita degli Studi di Udine, 33100 Udine,3 Italy, and AMGEN, Inc., Thousand Oaks, California2

Received 14 September 2000/Accepted 8 November 2000

Gas6 is a growth factor related to protein S that was identified as the ligand for the Axl receptor tyrosine kinase (RTK) family. In this study, we show that Gas6 induces a growth response in a cultured mammalian mammary cell line, C57MG. The presence of Gas6 in the medium induces growth after confluence and similarly causes cell cycle reentry of density-inhibited C57MG cells. We show that Axl RTK but not Rse is efficiently activated by Gas6 in density-inhibited C57MG cells. We have analyzed the signaling required for the Gas6 proliferative effect and found a requirement for PI3K-, S6K-, and Ras-activated pathways. We also demonstrate that Gas6 activates Akt and concomitantly inhibits GSK3 activity in a wortmannin-dependent manner. Interestingly, Gas6 induces up-regulation of cytosolic beta -catenin, while membrane-associated beta -catenin remains unaffected. Stabilization of beta -catenin in C57MG cells is correlated with activation of a T-cell factor (TCF)-responsive transcriptional element. We thus provide evidence that Gas6 is mitogenic and induces beta -catenin proto-oncogene stabilization and subsequent TCF/Lef transcriptional activation in a mammary system. These results suggest that Gas6-Axl interaction, through stabilization of beta -catenin, may have a role in mammary development and/or be involved in the progression of mammary tumors.

* Corresponding author. Mailing address: LNCIB, AREA Science Park, Padriciano 99, 34012 Trieste, Italy. Phone: 39-040398985. Fax: 39-040398990. E-mail: schneide{at}sci.area.trieste.it.

dagger Present address: Diabetes Research Laboratory, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Charlestown, MA 02129.

Molecular and Cellular Biology, February 2001, p. 902-915, Vol. 21, No. 3
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.3.902-915.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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