Calmodulin differentially modulates Smad1 and Smad2 signaling

Andreas Scherer, Jonathan M. Graff

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

The members of the Smad protein family are intracellular mediators of transforming growth factor β (TGF-β) signaling. Smad1 transduces bone morphogenetic protein signals, inducing formation of ventral mesoderm in Xenopus embryos, whereas Smad2 transduces activin/TGF-β signals, generating dorsal mesoderm. Calmodulin directly binds to many Smads and was shown to down-regulate Smad2 activity in a cell culture system (Zimmerman, C. M., Kariapper, M. S. T., and Mathews, L. S. (1997) J. Biol. Chem. 273, 677-680). Here, we extend those data and demonstrate that calmodulin alters Smad signaling in living embryos, increasing Smad1 activity while inhibiting Smad2 function. To characterize this regulation, we undertook a structure-function analysis and found that calmodulin binds to two distinct and conserved regions in both Smad1 and Smad2, Receptor tyrosine kinase signaling also modifies Smad activity (Kretzschmar, M., Doody, J., and Massagué, J. (1997) Nature 389, 618-622: Kretzschmar, M. Doody, J., Timokhina, I., and Massagué, J. (1999) Genes Dev. 13, 804-816: de Caestecker, M. P., Parks, W. T., Frank, C. J., Castagnino, P., Bottaro, D. P., Roberts, A. B., and Lechleider, R. J. (1998) Genes Dev, 12, 1587-1592. We show that calmodulin binding to Smads inhibits subsequent Erk2-dependent phosphorylation of Smads and vice versa. These observations suggest the presence of a cross-talk between three major signaling cascades as follows: Ca2+/calmodulin, receptor tyrosine kinase, and TGF-β pathways.

Original languageEnglish (US)
Pages (from-to)41430-41438
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number52
DOIs
StatePublished - Dec 29 2000

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Calmodulin
Transforming Growth Factors
Receptor Protein-Tyrosine Kinases
Mesoderm
Embryonic Structures
Genes
Smad Proteins
Activins
Bone Morphogenetic Proteins
Phosphorylation
Xenopus
Cell culture
Down-Regulation
Cell Culture Techniques

ASJC Scopus subject areas

  • Biochemistry

Cite this

Calmodulin differentially modulates Smad1 and Smad2 signaling. / Scherer, Andreas; Graff, Jonathan M.

In: Journal of Biological Chemistry, Vol. 275, No. 52, 29.12.2000, p. 41430-41438.

Research output: Contribution to journalArticle

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