Truncated activin type I receptor Alk4 isoforms are dominant negative receptors inhibiting activin signaling.
Activin, a member of the transforming growth factor beta (TGFbeta) superfamily of cytokines, inhibits cell proliferation in a variety of cell types. The functions of activin are mediated by type I and type II serine/threonine 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 Alk4 receptor isoforms are exclusively expressed in human pituitary tumors, and that the majority of such tumors did not exhibit activin-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-responsive reporter construct, 3TPLux. When each of these truncated Alk4 receptors was stably transfected into K562 cells, activin-induced expression of an endogenous gene, junB, was blocked, indicating that inhibition of gene expression also occurred at the chromosomal level. Furthermore, activin administration failed to cause growth inhibition and an increase of the G1 population in these cells. Coimmunoprecipitation experiments showed that the truncated Alk4 receptors formed complexes with type II activin receptors, but were not phosphorylated. These data indicate that the truncated activin type I receptors, predominantly expressed in human pituitary adenomas, function as dominant negative receptors to interfere with wild-type receptor function and block the antiproliferative effect of activin. This may contribute to uncontrolled pituitary cell growth and the development of human pituitary tumors.
Zhou
Y
Y
Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
Sun
H
H
Danila
D C
DC
Johnson
S R
SR
Sigai
D P
DP
Zhang
X
X
Klibanski
A
A
D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; D028341:Activins; D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D019556:COS Cells; D002455:Cell Division; D002460:Cell Line; D017930:Genes, Reporter; D016758:Genes, jun; D006801:Humans; D007265:Inhibins / Q000037:antagonists & inhibitors*; D020014:K562 Cells; D046911:Macromolecular Substances; D010766:Phosphorylation; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D017978:Receptors, Growth Factor / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D001426:Bacterial Proteins; C085427:LuxI protein, Bacteria; D046911:Macromolecular Substances; D020033:Protein Isoforms; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D028341:Activins; D007265:Inhibins; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II