Truncated activin type I receptor Alk4 isoforms are dominant negative receptors inhibiting activin signaling

Activin, a member of the transforming growth factor beta (TGF beta) superfa mily of cytokines, inhibits cell proliferation in a variety of cell types. The functions of activin are mediated by type I and type II serine/threonin e kinase receptors. The main type I receptor mediating activin signaling in human cells is ActRIB, also called Alk4. We have previously reported that several truncated AIk4 receptor isoforms are exclusively expressed in human pituitary tumors, and that the majority of such tumors did not exhibit act ivin-induced growth arrest in culture. We therefore studied the function of these truncated receptor isoforms. Transient expression of these truncated receptors inhibited activin-activated transcription from an activin-respon sive reporter construct, 3TPLux. When each of these truncated Alk4 receptor s was stably transfected into K562 cells, activin-induced expression of an endogenous gene, junB, was blocked, indicating that inhibition of gene expr ession also occurred at the chromosomal level. Furthermore, activin adminis tration failed to cause growth inhibition and an increase of the G(1) popul ation in these cells. Coimmunoprecipitation experiments showed that the tru ncated Alk4 receptors formed complexes with type II activin receptors, but were not phosphorylated. These data indicate that the truncated activin typ e I receptors, predominantly expressed in human pituitary adenomas, functio n as dominant negative receptors to interfere with wild-type receptor funct ion and block the antiproliferative effect of activin. This may contribute to uncontrolled pituitary cell growth and the development of human pituitar y tumors.