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Molecular and Cellular Biology, August 2005, p. 6921-6936, Vol. 25, No. 16
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.16.6921-6936.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Signaling Network of Transforming Growth Factor ß1, Protein Kinase C{delta}, and Integrin Underlies the Spreading and Invasiveness of Gastric Carcinoma Cells

Mi-Sook Lee,1 Tae Young Kim,1 Yong-Bae Kim,2 Sung-Yul Lee,1 Seong-Gyu Ko,2,{dagger} Hyun-Soon Jong,2 Tae-You Kim,1,2 Yung-Jue Bang,1,2 and Jung Weon Lee1,2*

Cancer Research Institute, Departments of Molecular and Clinical Oncology and,1 Tumor Biology, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea2

Received 23 November 2004/ Returned for modification 15 February 2005/ Accepted 24 May 2005

Integrin-mediated cell adhesion and spreading enables cells to respond to extracellular stimuli for cellular functions. Using a gastric carcinoma cell line that is usually round in adhesion, we explored the mechanisms underlying the cell spreading process, separate from adhesion, and the biological consequences of the process. The cells exhibited spreading behavior through the collaboration of integrin-extracellular matrix interaction with a Smad-mediated transforming growth factor ß1 (TGFß1) pathway that is mediated by protein kinase C{delta} (PKC{delta}). TGFß1 treatment of the cells replated on extracellular matrix caused the expression and phosphorylation of PKC{delta}, which is required for expression and activation of integrins. Increased expression of integrins {alpha}2 and {alpha}3 correlated with the spreading, functioning in activation of focal adhesion molecules. Smad3, but not Smad2, overexpression enhanced the TGFß1 effects. Furthermore, TGFß1 treatment and PKC{delta} activity were required for increased motility on fibronectin and invasion through matrigel, indicating their correlation with the spreading behavior. Altogether, this study clearly evidenced that the signaling network, involving the Smad-dependent TGFß pathway, PKC{delta} expression and phosphorylation, and integrin expression and activation, regulates cell spreading, motility, and invasion of the SNU16mAd gastric carcinoma cell variant.

* Corresponding author. Mailing address: Cancer Research Institute, College of Medicine, Seoul National University, 28, Yongon-dong, Chongno-gu, Seoul 110-799, Republic of Korea. Phone: 82-2-3668-7030. Fax: 82-2-766-4487. E-mail: jwl{at}snu.ac.kr.

{dagger} Present address: Laboratory of Clinical Biology and Pharmacogenomics, Department of Preventive Medicine, School of Oriental Medicine, Kyunghee University, Seoul 130-701, Republic of Korea.

Molecular and Cellular Biology, August 2005, p. 6921-6936, Vol. 25, No. 16
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.16.6921-6936.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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