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J. Biol. Chem., Vol. 279, Issue 45, 47379-47390, November 5, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/45/47379    most recent M402031200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sawhney, R. S. Articles by Brattain, M. G. Search for Related Content PubMed PubMed Citation Articles by Sawhney, R. S. Articles by Brattain, M. G. Social Bookmarking                      What's this?

Autocrine Transforming Growth Factor Regulates Cell Adhesion by Multiple Signaling via Specific Phosphorylation Sites of p70S6 Kinase in Colon Cancer Cells^*

Rajinder S. Sawhney, Michelle M. Cookson, Bhavya Sharma, Jennie Hauser, and Michael G. Brattain

From the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263

Recently, we showed that autocrine transforming growth factor (TGF) controls the epidermal growth factor receptor (EGFR)-mediated basal expression of integrin ₂, cell adhesion and motility in highly progressed HCT116 colon cancer cells. We also reported that the expression of basal integrin ₂ and its biological effects are critically controlled by the constitutive activation of the ERK/MAPK pathway (Sawhney, R. S., Sharma, B., Humphrey, L. E., and Brattain, M. G. (2003) J. Biol. Chem. 278, 19861–19869). In the present report, we further examine the downstream signaling mechanisms underlying EGFR/ERK signaling and integrin ₂ function in HCT116 cells. Selective MEK inhibitors attenuated TGF-mediated basal activation of p70S6K (S6K) specifically at Thr-389, indicating that this S6K site is downstream of ERK/MAPK signaling. Cells were treated with the selective protein kinase C (PKC) inhibitor bisindolylmaleimide to determine the role of PKC in S6K activation. The Thr-421 and Ser-424 phosphorylation sites of S6K were specifically inhibited by bisindolylmaleimide, which also blocked integrin ₂ expression, cell adhesion, and motility. These data establish a novel cell motility function of S6K via PKC activation in a cancer cell. In addition, we examined whether mammalian target of rapamycin signaling controls S6K activation. Rapamycin inhibited constitutive S6K phosphorylation specifically at Thr-389, Thr-421, and Ser-424 sites. The assignment of these phosphorylation sites on S6K to biological functions was unequivocally confirmed by transfection of cells with specific single phosphorylation site dominant negative mutants. These experiments show for the first time that autocrine TGF regulates cell adhesion function by multiple signaling pathways via specific phosphorylation sites of S6K in cancer cells.

Received for publication, February 24, 2004 , and in revised form, July 23, 2004.

^* This work was supported in part by National Institutes of Health Grants CA 16056, 54807, 34432, and 50457 and by the Shelby Rae Tengg Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Calton St., Buffalo, NY 14263. Tel.: 716-845-5874; Fax: 716-845-8857; E-mail: rajinder.sawhney{at}roswellpark.org. To whom correspondence may be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton St., Buffalo, NY 14263. Tel.: 716-845-3044; Fax: 716-845-8857; E-mail: michael.brattain{at}roswellpark.org.

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