Ligand-independent Activation of Transforming Growth Factor (TGF) β Signaling Pathways by Heteromeric Cytoplasmic Domains of TGF-β Receptors

doi:10.1074/jbc.271.22.13123

Ligand-independent Activation of Transforming Growth Factor (TGF) β Signaling Pathways by Heteromeric Cytoplasmic Domains of TGF-β Receptors*

Xin-Hua Feng and
Rik Derynck^‡

From the Departments of Growth and Development and Anatomy, Programs in Cell Biology and Developmental Biology, University of California, San Francisco, California 94143

^‡ To whom correspondence should be addressed. Tel.: 415-476-7322; Fax: 415-476-1499.

Abstract

Transforming growth factor β (TGF-β) transduces signals through two related serine/threonine kinase receptors, the type I and type II receptors, which have the ability to interact with each other. In the heteromeric complex, the type II receptor is the primary determinant of ligand binding and phosphorylates the cytoplasmic domain of the type I receptor. Using a chimeric receptor strategy, we and others have shown previously that a functional TGF-β receptor complex requires heteromerization of both extracellular and intracellular domains of type I and type II receptors. In the current study, we show that overexpression of two receptors carrying a heteromeric combination of cytoplasmic domains resulted in ligand-independent responses, further supporting the functional requirement of the two heterologous cytoplasmic domains in TGF-β signaling. Furthermore, coexpression of only the cytoplasmic domains of both the type I and II receptors or tethering the type II to the type I cytoplasmic domain activated TGF-β responses in a ligand-independent manner. In cotransfected COS-1 cells, both cytoplasmic domains are associated with each other. Our results indicate that the cytoplasmic domains of the type I and type II TGF-β receptors physically and functionally interact with each other in the heteromeric complex.

Footnotes

↵* This work was supported by Grant CA63101 from the NCI, National Institutes of Health (to R. D.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

TGF-β

transforming growth factor β

PAGE

polyacrylamide gel electrophoresis

ET

extracellular/transmembrane

PAI

plasminogen-activator inhibitor.
- Received November 2, 1995.
- Revision received February 9, 1996.