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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,
-Catenin Stabilization, and T-Cell Factor
Transcriptional Activation in Contact-Inhibited C57 Mammary
Cells
Sandro
Goruppi,1,
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
-catenin, while
membrane-associated
-catenin remains unaffected. Stabilization of
-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
-catenin proto-oncogene
stabilization and subsequent TCF/Lef transcriptional activation in a
mammary system. These results suggest that Gas6-Axl interaction,
through stabilization of
-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.

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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