Smad8 mediates the signaling of the receptor serine kinase

Smad8 mediates the signaling of the receptor serine kinase

Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, CA 92037

Contributed by Wylie Vale

Abstract

Smad proteins are critical intracellular mediators of signaling by growth and differentiation factors of the transforming growth factor β superfamily. We have isolated a member of the Smad family, Smad8, from a rat brain cDNA library and biochemically and functionally characterized its ability to transduce signals from serine kinase receptors. In Xenopus embryo, Smad8 is able to transcriptionally activate a subset of mesoderm target genes similar to those induced by the receptor serine kinase, activin receptor-like kinase (ALK)-2. Smad8 can be specifically phosphorylated by a constitutively active ALK-2 but not the related receptor serine kinase, ALK-4. In response to signaling from ALK-2, Smad8 associates with a common regulatory molecule, Smad4, and this association leads to a synergistic effect on gene transcription. Furthermore, Smad8 is able to rescue the expression of mesoderm genes blocked by truncated ALK-2 in the embryo. These results indicate that Smad8 can function as a downstream signaling mediator of ALK-2.

Footnotes

↵ * Y.C. and A.B. contributed equally to this paper.
↵ † To whom reprint requests should be addressed at: Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037. e-mail: vale{at}salk.edu.
Data deposition: The sequences reported in this paper have been deposited in the GenBank data base (accession nos. AF012347 and AF012245).
ABBREVIATIONS:

ALK,

activin receptor-like kinase;

TGF-β,

transforming growth factor β;

GS domain,

glycine- and serine-rich region;

HA,

hemagglutinin;

BMP,

bone morphogenetic protein;

CA,

constitutively active;

Xbra,

brachyury;

gsc,

goosecoid;

chd,

chordin;

DMZ,

dorsal marginal zone