Identification of Smad2, a Human Mad-related Protein in the Transforming Growth Factor β Signaling Pathway

doi:10.1074/jbc.272.5.2896

Identification of Smad2, a Human Mad-related Protein in the Transforming Growth Factor β Signaling Pathway*

From the^‡ Ludwig Institute for Cancer Research, Box 595, S-751 24 Uppsala, Sweden and
^¶ Laboratory of Cancer Genetics, Department of Pathology, Göteborg University, Sahlgrenska Hospital, S-413 45 Göteborg, Sweden

^§ To whom correspondence should be addressed. Tel.: 46-18-160400; Fax: 46-18-160420.

Abstract

Transforming growth factor-β (TGF-β) superfamily members are multifunctional cytokines that exert their effects via heteromeric complexes of two distinct serine and threonine kinase receptors. Drosophila mothers against decapentaplegic and related genes in Caenorhabditis elegans, Xenopus, and mammals were shown to function downstream in the intracellular signaling pathways of TGF-β superfamily members. Here we report the cloning of a Mad-related protein, termed Sma- and Mad-related protein 2 (Smad2). TGF-β stimulated the phosphorylation and nuclear translocation of Smad2 in nontransfected Mv1Lu cells. In addition, we demonstrated that TGF-β and activin mediated phosphorylation of Smad2 after its overexpression with appropriate type I and II receptors in COS cells. Smad2 and Smad1 were found to be broadly expressed in human tissues. Smad2 is closely linked to DPC4 on chromosome 18q21.1, a region often deleted in human cancers. Cells that lack Smad2 may escape from TGF-β-mediated growth inhibition and promote cancer progression.

Footnotes

↵* This work was supported in part by the Swedish Cancer Society. 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

ActR

activin receptor

BMP

bone morphogenetic protein

DPC4

deleted in pancreatic carcinoma; locus 4

EST

expression sequence tag

FISH

fluorescence in situ hybridization

Dpp

decapentaplegic

Mad

mothers against dpp

Smad

Sma- and Mad-related protein

MH

Mad homology

PAGE

polyacrylamide gel electrophoresis

RT

reverse transcription

PCR

polymerase chain reaction

TβR

TGF-β receptor

YAC

yeast artificial chromosome

kb

kilobase.
↵² S. Souchelnytskyi, unpublished results.
↵³ A. Nakao, unpublished results.
- Received August 12, 1996.
- Revision received October 30, 1996.