Responsiveness to transforming growth factor-beta (TGF-beta) restored by genetic complementation between cells defective in TGF-beta receptors I and II

Abstract

Selection of mutant MvlLu mink lung epithelial cells resistant to growth inhibition by transforming growth factor-@ (TGF-@) has led to the isolation of cell clones with distinct alterations in type I and I1 TGF-@ receptors.Certain mutant clones present a decreased number or complete loss of detectable type I receptor.Other clones show a loss and/or altered electrophoretic mobility of the type I1 receptor, with concomitant loss of the type I receptor.Using somatic cell hybridization analysis we demonstrate the recessive nature of these mutants with respect to the wild-type phenotype and define various mutant complementation groups.Among these, hybrids between cells that express only type I1 receptor (R mutants) and cells that express neither receptor type (DRa mutants) rescue wild-type expression of type I receptors.Moreover, these hybrids regain full responsiveness to TGF-81, as measured by inhibition of DNA synthesis as well as stimulation of fibronectin and plasminogen activator inhibitor-1 production.These results provide evidence for an interaction between TGF-@ receptor components I and I1 and show that, in MvlLu cells, expression of both receptor types is required for mediation of biological responses to TGF-Bl.The transforming growth factor-0 (TGF-0)' family includes several homologous polypeptides that act in a paracrine fashion to regulate proliferation, differentiation, and other functions of the cell (1,2).The mammalian homodimeric isoforms TGF-01, -02, and $33, and the heterodimer TGF-01.2bind with high affinity to a set of cell surface proteins that include the type I receptor, the type I1 receptor, and betaglycan (2).Receptor types I and I1 are cell surface glycoproteins of 53 and 70 kDa, respectively.They are expressed ubiquitously,