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Concomitant loss of transforming growth factor (TGF)-beta receptor types I and II in TGF-beta-resistant cell mutants
M Laiho1, M B Weis, J Massagué
1Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Abstract:
A panel of 71 chemically mutagenized Mv1Lu mink lung epithelial cell clones were selected based on their resistance to the growth inhibitory action of transforming growth factor beta 1 (TGF-beta 1) and TGF-beta 2. Characterization of TGF-beta receptors in these mutants indicates that the TGF-beta-binding membrane proteoglycan, betaglycan, is apparently normal in all of them. However, 14 of the mutant clones are defective in TGF-beta receptor type I, and 22 clones are simultaneously defective in receptor types I and II. The clones with type I receptor defects fall into two distinct phenotypes, called R and LR. The R phenotype is characterized by the lack of detectable type I receptors, and has been previously described (Boyd, F. T., and Massagué, J. (1989) J. Biol. Chem. 264, 2272-2278). LR mutants are characterized by expression of low levels of type I receptor and are, like the R mutants, completely resistant to growth inhibition by TGF-beta 1 or -beta 2. Mutant clones that are simultaneously defective in receptor types I and II fall into three distinct phenotypes. These included DRa mutants which are characterized by lack of detectable receptor types I and II, DRb mutants which are characterized by low expression of both receptor types and an anomalously fast electrophoretic mobility of the type II receptor protein. All mutants that have a low level of type II receptor are also defective in type I receptor. In addition to the loss of growth inhibitory response, the receptor-defective mutants described here have lost all other responses to TGF-beta 1 and -beta 2 known to occur in parental Mv1Lu cells. The defects present in these mutant clones are not encountered in clones isolated from nonmutagenized parental Mv1Lu cells or in mutagenized cells that had not been exposed to selection with TGF-beta. The results implicate TGF-beta receptor types I and II in the mediation of a common set of cellular responses to TGF-beta. Furthermore, the high relative frequency of isolation of DR mutants raises the possibility that receptor types I and II interact as part of a common signaling TGF-beta receptor complex.
Insights
Researchers identified mutations in transforming growth factor beta (TGF-beta) receptors I and II, crucial for cell growth regulation. These TGF-beta receptor defects block cellular responses, suggesting they function together in a signaling complex.
Area of Science:
- Cell Biology
- Molecular Biology
- Signal Transduction
Background:
- Transforming growth factor beta (TGF-beta) is a key regulator of cell growth and differentiation.
- Cellular responses to TGF-beta are mediated by specific cell surface receptors.
- Understanding TGF-beta receptor function is critical for deciphering its role in various biological processes.
Purpose of the Study:
- To investigate the roles of TGF-beta receptor types I and II in mediating cellular responses.
- To characterize mutations affecting TGF-beta receptor function in Mv1Lu mink lung epithelial cells.
- To explore the potential interaction of TGF-beta receptor types I and II in a signaling complex.
Main Methods:
- Chemical mutagenesis of Mv1Lu cells followed by selection for resistance to TGF-beta 1 and TGF-beta 2.
- Characterization of TGF-beta receptor expression and function in isolated mutant clones.
- Phenotypic analysis of receptor-defective mutants to assess TGF-beta signaling pathways.
Main Results:
- Mutant clones defective in TGF-beta receptor type I (14 clones) or both types I and II (22 clones) were identified.
- Distinct phenotypes were observed, including complete absence or low expression of receptor type I, and absence or altered expression of receptor type II.
- All identified receptor defects resulted in complete resistance to TGF-beta's growth inhibitory effects and other known cellular responses.
Conclusions:
- TGF-beta receptor types I and II are essential for mediating a common set of cellular responses to TGF-beta.
- The high frequency of double receptor mutants suggests that TGF-beta receptor types I and II may interact within a common signaling complex.
- These findings provide insights into the molecular mechanisms of TGF-beta signal transduction.