Evidence for a Role of Rho-like GTPases and Stress-activated Protein Kinase/c-Jun N-terminal Kinase (SAPK/JNK) in Transforming Growth Factor β-mediated Signaling

doi:10.1074/jbc.272.3.1429

Evidence for a Role of Rho-like GTPases and Stress-activated Protein Kinase/c-Jun N-terminal Kinase (SAPK/JNK) in Transforming Growth Factor β-mediated Signaling*

From ^‡ INSERM U 55, Institut Fédératif de Recherche du Centre Hospitalo-Universitaire Saint-Antoine, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571, Paris Cedex 12, France and the
^¶Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School and Howard Hughes Medical Institute, Worcester, Massachusetts 01605

^∥To whom correspondence should be addressed. Tel.: 33-1-43-45-34-77; Fax: 33-1-49-28-46-94.

Abstract

Transforming growth factor β (TGF-β) is a multifunctional factor that induces a wide variety of cellular processes which affect growth and differentiation. TGF-β exerts its effects through a heteromeric complex between two transmembrane serine/threonine kinase receptors, the type I and type II receptors. However, the intracellular signaling pathways through which TGF-β receptors act to generate cellular responses remain largely undefined. Here, we report that TGF-β initiates a signaling cascade leading to stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) activation. Expression of dominant-interfering forms of various components of the SAPK/JNK signaling pathways including Rho-like GTPases, mitogen-activated protein kinase (MAPK) kinase kinase 1 (MEKK1), MAPK kinase 4 (MKK4), SAPK/JNK, and c-Jun abolishes TGF-β-mediated signaling. Therefore, the SAPK/JNK activation contributes to TGF-β signaling.

Footnotes

↵^§ These two authors contributed equally to this work.
↵* This work was supported by INSERM. 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:

MAPK

mitogen-activated protein kinase

SAPK

stress-activated protein kinase

JNK

c-Jun N-terminal kinases

MEKK1

MAPK kinase kinase 1

MKK4

MAPK kinase 4

TGF-β

transforming growth factor-β

MAPKKK

MAPKK kinase

BMP4

bone morphogenetic protein 4

FCS

fetal calf serum

HA

hemagglutinin

GST

glutathione S-transferase

MOPS

4-morpholinepropanesulfonic acid.
- Received November 6, 1996.