Negative regulation of activin signal transduction.

Activin is a member of the transforming growth factor β (TGFβ) superfamily. While it was originally isolated as a gonadal factor to regulate secretion of follicle-stimulating hormone (FSH) from the pituitary, it also has nonreproductive roles in immune responses, metabolism, tumorigenesis, and stem cell differentiation. Activin signaling is initiated by ligand-induced formation of a heteromeric complex of type I and type II transmembrane serine/threonine kinase receptors. The activated activin receptors phosphorylate the receptor-regulated Smads, Smad2 and Smad3, which subsequently form a complex with the common mediator, Smad4, and translocate into the nucleus for the transcriptional regulation of specific target genes in cooperation with DNA-binding cofactors and transcriptional coactivators. Activin signaling is controlled both extracellularly and intracellularly by diverse mechanisms to fine tune its duration and strength. This chapter summarizes current understanding of how activin signaling pathway is negatively regulated inside and outside the cells.