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Integrin-Dependent Cell Growth and Survival Are Mediated by Different Signals in Thyroid Cells

Dipartimento di Biologia e Patologia Cellulare e Molecolare (M.I., V.A., A.C., T.D.M., G.R., M.V.), Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica (G.F.), e Cattedra di Nefrologia (M.A.), Università Federico II, 80131 Naples, Italy; and Centro di Endocrinologia ed Oncologia Sperimentale "G. Salvatore" (C.M., G.R.), Consiglio Nazionale delle Ricerche, 80131 Naples, Italy

Address all correspondence and requests for reprints to: Mario Vitale, M.D., Dipartimento di Biologia e Patologia Cellulare e Molecolare, Via S. Pansini 5, 80131 Napoli, Italy. E-mail: mavitale{at}unina.it.

Cell adhesion to extracellular matrix regulates proliferation and survival of several cell types including epithelial thyroid cells. Activation of integrin receptors by binding to extracellular matrix generates a complex cell type-dependent signaling. Adhesion to extracellular matrix induces proliferation and survival in primary cultures of thyroid cells and induces survival in immortalized human thyrocytes. In this study we demonstrate that in immortalized human thyrocyte cells, adhesion to immobilized fibronectin (FN) stimulates DNA synthesis and proliferation through the p21Ras/MAPK pathway, whereas cell survival is mediated by phosphatidylinositol 3-kinase (PI3K) signal pathway. Integrin activation by immobilized FN induced phosphorylation of pp125 focal adhesion kinase and paxillin and induced the formation of focal adhesion kinase/Grb-2/Sos complex. Western blot and in vitro kinase assay demonstrated the activation of Ras and the p44/p42 MAPK/ERK1/2. Inhibition of p21Ras activity and inhibition of MAPK enzymatic activity completely arrested cell growth but did not induce cell death. Integrin activation by cell adhesion to FN also induced activation of PI3K. Inhibition of PI3K enzymatic activity induced apoptosis demonstrated by annexin V-binding assay and loss of cellular DNA content. These results demonstrate that in thyroid cells adhesion to FN regulates proliferation through the p21Ras/MAPK signal pathway, whereas integrin-mediated cell survival is mediated by PI3K.

This work was partly supported by Ministero dell’Università e della Ricerca Scientifica (to G.F.), Consiglio Nazionale delle Ricerche (CNR; to M.V.), and Fondazione Italiana per la Ricerca sul Cancro (FIRC; to T.D.M.).

Abbreviations: ECL, Enhanced chemiluminescence; ECM, extracellular matrix; FAK, focal adhesion kinase; FCS, fetal calf serum; FN, fibronectin; GFP, green lantern fluorescent protein; MAPKK, MAPK-activating kinase; MBP, myelin basic protein; PI3K, phosphatidylinositol 3-kinase; RBD, Ras-binding domain peptide; RGD, arginine-glycine-aspartic acid; TAD-2, immortalized human thyrocyte; TCA, trichloroacetic acid.

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