Requirement of Transforming Growth Factor-β (TGF-β) Type II Receptor for TGF-β-induced Proliferation and Growth Inhibition

Stephen L Young,Yun Zhao

doi:10.1074/jbc.271.5.2369

Abstract

Growth regulation of fibroblasts is important for lung development and repair of lung injury. In this study, we investigated the role of transforming growth factor-beta (TGF-beta) type II receptor in the TGF-beta-dependent proliferative response of lung fibroblasts. TGF-beta stimulated the proliferation of adult lung fibroblasts at a low concentration (1 ng/ml), but inhibited the growth of fetal lung fibroblasts in a dose-dependent fashion (0.1-10 ng/ml). Cross-linking and Northern analysis demonstrated that the two lung fibroblast cell lines expressed the TGF-beta type I receptor (T beta RI) and type II receptor (T beta RII). We overexpressed in lung fibroblasts a truncated derivative of T beta RII that lacked the cytoplasmic serine/threonine kinase domain (T beta RII delta K). T beta RII delta K was a dominant-negative inhibitor of TGF-beta signal transduction blocking not only TGF-beta-induced mitogenic action upon adult lung fibroblasts but also TGF-beta-induced growth inhibition of fetal lung fibroblasts. The results indicate that the type II receptor is indispensable for mediating both the mitogenic and antiproliferative effects of TGF-beta upon lung fibroblasts.

Highlights

Growth regulation of fibroblasts is important for lung development and repair of lung injury
The adult rat lung fibroblast cell line was responsive to the growth stimulation of TGF-␤ as expected of most fibroblast cells, whereas fetal rat lung fibroblasts displayed an unexpected response, growth inhibition (Fig. 1)
The effects of transforming growth factor-␤ (TGF-␤)1 on the proliferation of adult lung fibroblasts were dependent on concentration (Fig. 1A)

Summary

Introduction

Growth regulation of fibroblasts is important for lung development and repair of lung injury. T␤RII⌬K was a dominant-negative inhibitor of TGF-␤ signal transduction blocking TGF-␤-induced mitogenic action upon adult lung fibroblasts and TGF␤-induced growth inhibition of fetal lung fibroblasts. Mv1Lu mink lung epithelial cells are highly responsive to the growth inhibition of TGF-␤. To further determine the role of T␤RII in modulating the growth stimulation effects of TGF-␤, we transfected into rat lung fibroblast cells an expression plasmid containing rat T␤RII cDNA that was lacking the kinase domain. Overexpression of the dominant-negative T␤RII mutant blocked both the stimulating and the inhibitory effects of TGF-␤ on rat lung fibroblasts. These experiments provide evidence for a functional role of T␤RII in TGF-␤-induced proliferation and growth inhibition of lung fibroblasts

Methods

Results

Conclusion