ISPO

Transforming growth factor-beta regulates the expression of E-cadherin through extracellular matrix remodeling and focal adhesion kinase.

S Chakrabarty, PhD

University of Texas, M.D. Anderson Cancer Center, Houston, Texas United States

Transforming growth factor-beta (TGFB) induces extracellular matrix (ECM) remodeling in a protein kinase C alpha-dependent manner and suppresses the malignant phenotype of TGFB-responsive human colon carcinoma Moser cells (Lab. Invest. 78: 413, 1998). One of the tumor-suppressive function of TGFB is the induction of the cell-cell adhesion and tumor-suppressive molecule E-cadherin (J. Cell. Physiol. 187: 188, 2001). The purpose of this investigation was to determine how TGFB induces the expression of E-cadherin. We found that disrupting ECM remodeling using an antisense expression construct targeting PKC alpha disrupted the induction of E-cadherin by TGFB. Antibody-blocking experiments using antibodies directed against the adhesion molecules fibronectin or laminin or the integrin receptors for these molecules were then used to disrupt cell-matrix adhesion and focal adhesion contacts. Disruption of these physiologic processes disrupted the ability of TGFB to induce E-cadherin. Because focal adhesion kinase (FAK) is a major signaling molecule in focal adhesion contacts, the functional significance of FAK in the induction of E-cadherin by TGFB was determined. Inactivation of FAK by an antisense FAK expression construct or a dominant negative inhibitor of FAK blocked the induction of E-cadherin by TGFB. It is concluded that the induction of E-cadherin by TGFB requires proper ECM remodeling and formation of focal adhesion contacts which serve to activate FAK and generate the signals that lead to the induction of E-cadherin.

KEY WORDS: colon carcinoma, cell-matrix and cell-cell adhesion.

For more information, contact schakrab@mdanderson.org

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Molecular Pathology.

http://www.cancerprev.org/Journal/Issues/26/101/991/4159