Open Access Open Badges Research article

Cloning of a novel signaling molecule, AMSH-2, that potentiates transforming growth factor β signaling

Nieves Ibarrola1, Irina Kratchmarova2, Daisuke Nakajima3, William P Schiemann4, Aristidis Moustakas5, Akhilesh Pandey1* and Matthias Mann2*

Author Affiliations

1 McKusick-Nathans Institute of Genetic Medicine and Department of Biological Chemistry, Johns Hopkins University, Baltimore, MD 21205, U.S.A

2 Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, DK-5230, Denmark

3 Department of Genome Informatics, Kazusa DNA Research Institute, Chiba 292-0812, Japan

4 Department of Pediatrics, National Jewish Medical and Research Center, Goodman Building, K1011, Denver, CO 80206, U.S.A

5 Ludwig Institute for Cancer Research, Uppsala, SE-751 24, Sweden

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BMC Cell Biology 2004, 5:2  doi:10.1186/1471-2121-5-2

Published: 19 January 2004



Transforming growth factor-βs (TGF-βs), bone morphogenetic proteins (BMPs) and activins are important regulators of developmental cell growth and differentiation. Signaling by these factors is mediated chiefly by the Smad family of latent transcription factors.


There are a large number of uncharacterized cDNA clones that code for novel proteins with homology to known signaling molecules. We have identified a novel molecule from the HUGE database that is related to a previously known molecule, AMSH (

olecule with the
3 domain of STAM), an adapter shown to be involved in BMP signaling. Both of these molecules contain a coiled-coil domain located within the amino-terminus region and a JAB (Domain in
un kinase
ctivation domain
inding protein and proteasomal subunits) domain at the carboxy-terminus. We show that this novel molecule, which we have designated AMSH-2, is widely expressed and its overexpression potentiates activation of TGF-β-dependent promoters. Coimmunoprecipitation studies indicated that Smad7 and Smad2, but not Smad3 or 4, interact with AMSH-2. We show that overexpression of AMSH-2 decreases the inhibitory effect of Smad7 on TGF-β signaling. Finally, we demonstrate that knocking down AMSH-2 expression by RNA interference decreases the activation of 3TP-lux reporter in response to TGF-β.


This report implicates AMSH and AMSH-2 as a novel family of molecules that positively regulate the TGF-β signaling pathway. Our results suggest that this effect could be partially explained by AMSH-2 mediated decrease of the action of Smad7 on TGF-β signaling pathway.

Signal transduction; bioinformatics; serine/threonine kinase; phosphorylation