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Results for “Activin Receptors, Type I”

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PubMed2002

Overexpression of wild-type activin receptor alk4-1 restores activin antiproliferative effects in human pituitary tumor cells.

Activin is a member of the TGF beta family of cytokines involved in the control of cell proliferation. We have previously shown that the majority of clinically nonfunctioning pituitary tumors do not respond to activin-induced growth suppression. Human pituitary tumors specifically express alternatively spliced activin type I receptor Alk4 mRNAs, producing C-terminus truncated isoforms designated Alk4-2, 4-3, and 4-4. However, it is not known whether these truncated activin receptors suppress activin effects on cell proliferation in human pituitary cells. Therefore, we investigated activin signaling in a human pituitary tumor cell line, HP75, derived from a clinically nonfunctioning pituitary tumor. HP75 cells express activin A mRNA and secrete activin A, as measured by ELISA and a functional bioassay. TGF beta administration decreases the proliferation of HP75 cells, suggesting that the signaling pathway shared by TGF beta and activin is functional in this cell line. However, activin neither inhibits cell proliferation nor stimulates reporter gene expression in HP75 cells, indicating that activin signaling is specifically blocked at the receptor level. HP75 cells express all truncated activin type I receptor Alk4 isoforms, as determined by RT-PCR. Because truncated Alk4 receptor isoforms inhibit activin signaling by competing with the wild-type receptor for binding to activin type II receptors, we hypothesized that overexpression of wild-type activin type I receptor will restore activin signaling. In HP75 cells, cotransfection of the wild-type activin type I receptor Alk4-1 expression vector increases activin-responsive reporter activity. Furthermore, transfection with wild-type activin receptor type I results in activin-mediated suppression of cell proliferation. These data indicate that truncated Alk4 isoforms interfere with activin signaling pathways and thereby may contribute to uncontrolled cell growth. Overexpression of the wild-type Alk4-1 receptor restores responsiveness to activin in human pituitary tumor-derived cells.

Activin Receptors, Type I↗

PubMed1993

Cloning and characterization of a transmembrane serine kinase that acts as an activin type I receptor.

Activin type II receptors are transmembrane protein-serine/threonine kinases. By using a reverse-transcription PCR assay to screen for protein kinase sequences, we isolated a cDNA clone, activin X1 receptor, from rat brain that encodes a 55-kDa transmembrane protein-serine kinase which is structurally related to other receptors in this kinase subfamily. The predicted protein consists of 509 amino acids, and the kinase domain shows 40% and 37% identity to the activin and transforming growth factor beta type II receptors, respectively. No activin-binding was observed when activin X1 receptor was expressed alone in COS-M6 cells; however, coexpression with type II activin receptors gave rise to a 68-kDa affinity-labeled complex in addition to the 85-kDa type II receptor complex. The size of this cross-linked band is consistent with the size of the type I activin receptor; furthermore, activin X1 receptor associated with type II receptors, as judged by coimmunoprecipitation with type II receptor antibodies. These data suggest that activin X1 receptor can serve as an activin type I receptor and that the diverse biological effects of activins may be mediated by a complex formed by the interaction of two transmembrane protein-serine kinases.

Activin Receptors↗

PubMed1998

Identification of a novel type II activin receptor, type IIA-N, induced during the neural differentiation of murine P19 embryonal carcinoma cells.

We have identified a novel type II activin receptor, called type IIA-N, the expression of which was induced during the neural differentiation of murine P19 embryonal carcinoma cells (P19 cells). P19 cells differentiate into several cell types dependent on the culture conditions. The induction of type IIA-N mRNA occurred predominantly in conjunction with neural differentiation. Sequence analysis of a cDNA clone for type IIA-N indicated that type IIA-N had a 24 bp insertion in the juxtamembrane region of the type IIA activin receptor suggesting that it is an alternative splicing product of the type IIA gene. Type IIA-N was also identified in human and Xenopus, and the amino acid sequences of three species were completely conserved. The expression of type IIA-N mRNA was specifically detected in neuroblastoma cells among several activin responsive cell lines. In vivo expression of type IIA-N mRNA was detected only in the neural tissues such as brain and spinal cord in adult mouse, by RT-PCR. Furthermore, its expression in developing Xenopus embryos was restricted to the neurula and later stages. These results suggest that the expression of type IIA-N is specific to neural cells and mediates neural differentiation-specific activin signaling.

Activin Receptors↗

PubMed1998

The role of activin type I receptors in activin A-induced growth arrest and apoptosis in mouse B-cell hybridoma cells.

Activins transduce their signals by binding to activin type I receptors and activin type II receptors, both of which contain a serine/threonine kinase domain. In this study, we established stable transfectants expressing two types of activin receptors, ActRI and ActRIB, to clarify the role of these receptors in activin signalling for growth inhibition in HS-72 mouse B-cell hybridoma cells. Over-expression of ActRI suppressed activin A-induced cell-cycle arrest in the G1 phase caused by inhibition of retinoblastoma protein phosphorylation through induction of p21CIP1/WAF1, a cyclin-dependent kinase inhibitor, and subsequent apoptosis. In contrast, HS-72 clones that over-expressed ActRIB significantly facilitated activin A-induced apoptosis. These results indicate that ActRI and ActRIB are distinct from each other and that the ActRI/ActRIB expression ratio could regulate cell-cycle arrest in the G1 phase and subsequent apoptosis in HS-72 cells induced by activin A.

Activin Receptors, Type I↗

PubMed1995

Different phenotypes for mice deficient in either activins or activin receptor type II.

Activins are believed to initiate a signal transduction cascade by binding to serine/threonine kinase receptors types I and II. Activins bind to several different receptors in vitro, but the significance of this interaction in vivo has not been confirmed. To test the function of the type II activin receptor (ActRcII) in mammalian development and reproduction, we generated a null mutation in the ActRcII gene in mice using embryonic stem cell technology. We expected ActRcII-deficient mice to phenocopy activin-deficient mice. A few ActRcII-deficient mice had skeletal and facial abnormalities reminiscent of the Pierre-Robin syndrome in humans, but most lacked these defects and developed into adults; their follicle-stimulating hormone was suppressed, and their reproductive performance was defective. These findings confirm a role of ActRcII in activin signalling in pituitary gonadotrophs. The striking lack of overlap between phenotypes of ActRcII-deficient and activin-deficient mice suggests that the ligands that signal through ActRcII during embryonic development are not activins.

Activin Receptors↗

PubMed1994

Peritubular myoid cells from immature rat testes secrete activin-A and express activin receptor type II in vitro.

The expression of activin type II and IIB receptors and inhibin alpha-, beta A-, and beta B-subunit messenger RNAs (mRNAs), and the secretion of immunoreactive and bioactive activin during culture of testicular peritubular myoid cells and peritubular myoid cell lines were studied. Cultured peritubular myoid cells and cell lines expressed high levels of inhibin beta A-subunit mRNA and some inhibin alpha- and beta B-subunit mRNA. Activin receptor type II mRNA was also detected, whereas activin receptor type IIB mRNA expression was not found. Expression of the beta A-subunit mRNA was present immediately after isolation of the cells and increased during culture in Eagle's Minimum Essential Medium containing 10% fetal calf serum. beta A-Subunit mRNA expression was not regulated by the synthetic androgen R1881. Western blotting of peritubular myoid cell- and peritubular cell line-conditioned media with a polyclonal antiserum against recombinant activin-A revealed the presence of 25-kilodalton activin-A, whereas activin bioactivity was detected using the animal cap assay. Because of the secretion of activin-A by peritubular myoid cells, the effects of recombinant activin-A on Sertoli cell inhibin and transferrin secretion were examined. Activin-A stimulated both basal and FSH-stimulated inhibin and transferrin production by Sertoli cells after 72 h of culture. These effects resemble the effects of the testicular paracrine factor PmodS on Sertoli cell function. It is concluded that activin-A is secreted by peritubular cells in vitro and that activin-A shares a number of effects on Sertoli cell function with PmodS.

Activin Receptors↗

PubMed1994

Bovine activin receptor type II cDNA: cloning and tissue expression.

The cDNA encoding the bovine activin type II receptor has been cloned by reverse transcription-polymerase chain reaction (RT-PCR) amplification of a bovine testicular RNA preparation. Sequence comparisons of the bovine activin type II receptor with its human, mouse and rat homologues show strong evolutionary conservation at the nucleotide level of 94.9%, 93.5%, 92.9% and at the amino acid level of 98.6%, 99.0%, 98.8%, respectively. Bovine activin type II receptor mRNA is widely but not strongly expressed in reproductive tissues, with a major RNA band at 6 kb and minor bands at 5 kb and 3 kb. The differential levels of expression observed in these tissues suggest that levels of bActRII gene expression are regulated. Furthermore, we have observed decreasing levels of the bovine activin type II receptor mRNA with testes maturation.

Activin Receptors↗

PubMed2000

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.

Activin Receptors, Type I↗

PubMed1999

Left-right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB.

Targeted disruption of the mouse activin receptor type IIB gene (Acvr2b) results in abnormal left-right (LR) axis development among Acvr2b-/- homozygotes [Oh and Li, 1997: Genes Dev 11:1812-1826]. The resulting malformations include atrial and ventricular septal defects, right-sided morphology of the left atrium and left lung, and spleen hypoplasia. Based on these results, we hypothesized that mutations in the type IIB activin receptor gene are associated with some cases of LR axis malformations in humans. We report here characterization of the ACVR2B genomic structure, analysis of ACVR2B splice variants, and screening for ACVR2B mutations among 112 sporadic and 14 familial cases of LR axis malformations. Two missense substitutions have been identified, one of which appears in two unrelated individuals. Neither of these nucleotide changes has been found in 200 control chromosomes. We conclude that ACVR2B mutations are present only rarely among human LR axis malformation cases.

Activin Receptors, Type II↗

PubMed1995

Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects.

Proteins in the TGF-beta superfamily transduce their effects through binding to type I and type II serine/threonine kinase receptors. Osteogenic protein-1 (OP-1, also known as bone morphogenetic protein-7 or BMP-7), a member of the TGF-beta superfamily which belongs to the BMP subfamily, was found to bind activin receptor type I (ActR-I), and BMP receptors type IA (BMPR-IA) and type IB (BMPR-IB) in the presence of activin receptors type II (ActR-II) and type IIB (ActR-IIB). The binding affinity of OP-1 to ActR-II was two- to threefold lower than that of activin A. A transcriptional activation signal was transduced after binding of OP-1 to the complex of ActR-I and ActR-II, or that of BMPR-IB and ActR-II. These results indicate that ActR-II can act as a functional type II receptor for OP-1, as well as for activins. Some of the known biological effects of activin were observed for OP-1, including growth inhibition and erythroid differentiation induction. Compared to activin, OP-1 was shown to be a poor inducer of mesoderm in Xenopus embryos. Moreover, follistatin, an inhibitor of activins, was found to inhibit the effects of OP-1, if added at a 10-fold excess. However, certain effects of activin, like induction of follicle stimulating hormone secretion in rat pituitary cells were not observed for OP-1. OP-1 has overlapping binding specificities with activins, and shares certain but not all of the functional effects of activins. Thus, OP-1 may have broader effects in vivo than hitherto recognized.

Activin Receptors↗

PubMed2001

Activin type II receptors in embryonic dorsal root ganglion neurons of the chicken.

Activin induces neuropeptide expression in chicken ciliary ganglion neurons. To determine if activin might also influence neuropeptide expression in developing sensory neurons, we examined whether type II activin receptors are expressed during embryonic development of the chicken dorsal root ganglia (DRG), and also examined the effects of activin on neuropeptide expression in cultured DRG neurons. Using reverse transcription polymerase chain reaction (rtPCR), we detected mRNAs for both the activin receptors type IIA (ActRIIA) and type IIB (ActRIIB) in DRG from embryonic day 7 through posthatch day 1. With in situ hybridization, we found that morphologically identifiable neurons express mRNAs for both ActRIIA and ActRIIB. With developmental age, a subset of neurons that hybridizes more intensely with riboprobes to these receptor mRNAs becomes evident. A similar pattern of expression is observed with immunocytochemical staining using antisera against activin type II receptors. To examine whether embryonic DRG cells respond to activin we treated dissociated cultures of DRG with activin A and assessed the expression of vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP) mRNAs using semiquantitative rtPCR. Activin treatment results in an increase in VIP mRNA, but does not affect CGRP mRNA levels. These observations indicate that neurons in the embryonic chicken DRG can respond to activin and suggest that activin has the potential to play a role in the development and function of DRG sensory neurons.

Activin Receptors, Type II↗

PubMed2006

Generation of activin receptor type IIB isoform-specific hypomorphic alleles.

Activin receptor type IIB (Acvr2b) mediates multiple signals for transforming growth factor-beta (TGF-beta) family members, including Activin, Nodal, Bmp7, Gdf1, Gdf3, Myostatin (Gdf8), and Gdf11. Mouse Acvr2b gene generates four transcriptional isoforms (Acvr2b(1-4)) via alternative splicing of two sequence domains located at the juxtaposition of the transmembrane domain. To investigate whether these splicing domains are essential for signal transduction of the Acvr2b receptor in vivo, we have generated a strain of mutant mice (Acvr2b(4/4)) which produce only the Acvr2b(4) isoform, which lacks both splicing domains. Most homozygous Acvr2b(4(neo)/4(neo)) mice, in which a neomycin-resistant cassette was inserted in Intron 4 displayed a mild form of anterior vertebral transformations. However, the penetrance of the vertebral defect was dramatically decreased when the neomycin-resistant cassette was deleted. These results suggest that the Acvr2b(4) isoform is capable of compensating for the deficiency of the other three isoforms. In the absence of its subfamily receptor Acvr2a, however, the development of Acvr2b(4/4) mice was arrested at the gastrulation stage, recapitulating the Acvr2a(-/-); Acvr2b(+/-) mutant phenotype. In this study, we demonstrate that this phenomenon is most likely due to the reduction in the expressed Acvr2b(4) levels rather than to the functional deficiency of the Acvr2b(4) isoform itself.

Activin Receptors, Type II↗

PubMed1992

Differential expression of inhibin subunits and follistatin, but not of activin receptor type II, during early murine embryonic development.

Activins are known to be potentially important regulators of early developmental processes in amphibians, birds, and mammalians. In this study we report the expression of the inhibin subunits, including those that make up activin, the activin-binding protein follistatin, and activin receptor type II in several in vitro systems that model early murine embryonic development, namely embryonic stem (ES) cells, embryonal carcinoma (EC) cells, and their differentiated derivatives. In addition, we examine the expression pattern of these factors in different stages of the mouse embryo itself. Expression of inhibin alpha and beta A subunits is restricted to certain differentiated cell types, while beta B subunits are expressed in both differentiated and undifferentiated cells. Our results further indicate a change in the expression pattern of inhibin subunits during early development from beta B at the blastocyst stage largely to beta A in postgastrulation embryos. This is similar to the expression pattern at equivalent stages of Xenopus and chick development. Expression of the activin-binding protein follistatin is altered by the induction of differentiation of P19 EC and ES cells by several factors, including retinoic acid. In contrast to the inhibin subunits and follistatin, activin receptor levels are not influenced by differentiation in these cell types. The results of this study demonstrate that the inhibin subunits and follistatin, but not the activin receptor type II, are differentially expressed during early murine development and suggest that the different forms of activin/inhibin are involved in the regulation of different developmental processes.

Activin Receptors↗

PubMed2004

Loss of activin receptor type 2 protein expression in microsatellite unstable colon cancers.

BACKGROUND & AIMS: Colorectal tumors manifesting high-frequency microsatellite instability (MSI-H) develop genetically as a consequence of mutations in genes harboring repetitive DNA sequences. The activin type 2 receptor (ACVR2), possessing 2 polyadenine coding sequences, was identified as a mutational target, but it is not clear if expression is abrogated. Here, we analyzed MSI-H colorectal cancers for ACVR2 mutation and expression to assess if biallelic inactivation occurs. METHODS: All 54 MSI-H colon cancers and 20 random microsatellite stable (MSS) tumors from a population-based cohort of 503 patients were analyzed for mutations in 2 A(8) tracts (exon 3 and 10) of ACVR2 and the A(10) tract of transforming growth factor beta receptor 2 (TGFBR2). Additionally, we sequenced exon 10 of ACVR2 in select cancers. ACVR2 expression was determined by immunohistochemistry using an antibody targeting an epitope beyond the predicted truncated protein. RESULTS: Forty-five of 54 MSI-H cancers (83%) showed mutation (A(8) to A(7)) in the polyadenine tract of exon 10 compared with no MSS tumors. Of tumors with mutant ACVR2, 62% lacked protein expression but all MSS and MSI-H tumors with wild-type ACVR2 expressed protein. We found no evidence of loss of heterozygosity at the ACVR2 locus in MSS tumors. Comparatively, 69% of MSI-H cancers had frameshift mutation in TGFBR2. CONCLUSIONS: ACVR2 mutations are highly frequent in MSI-H colon cancers and in most cases cause loss of ACVR2 expression, indicating biallelic inactivation of the gene. Loss of activin signaling through mutation of ACVR2, similar to observations with TGFBR2, may be important in the genesis of MSI-H colorectal cancer.

Activin Receptors, Type II↗

PubMed1997

Differential effects on Xenopus development of interference with type IIA and type IIB activin receptors.

One candidate for a mesoderm-inducing factor in early amphibian development is activin, a member of the TGF beta family. Overexpression of a truncated form of an activin receptor Type IIB abolishes activin responsiveness and mesoderm formation in vivo. The Xenopus Type IIA activin receptor XSTK9 differs from the Type IIB receptor by 43 and 25% in extracellular and intracellular domains respectively, suggesting the possibility of different functions in vivo. In this paper, we compare the Type IIA receptor with the Type IIB to test such a possibility. Simple overexpression of the wild-type receptors reveals minimal differences, but experiments with dominant negative mutants of each receptor show qualitatively distinct effects. We show that while truncated (kinase domain-deleted) Type IIB receptors cause axial defects as previously described, truncated type IIA receptors cause formation of secondary axes, similar to those seen by overexpression of truncated receptors for BMP-4, another TGF beta family member. Furthermore, in animal cap assays, truncated type IIB receptors inhibit induction of all mesodermal markers tested, while truncated type IIA receptors suppress induction only of ventral markers; the anterior/dorsal marker goosecoid is virtually unaffected. The suppression of ventral development by the type IIA truncated receptor suggests either that the truncated Type IIA receptor interferes with ventral BMP pathways, or that activin signaling through the Type IIA receptor is necessary for ventral patterning.

Activin Receptors↗

PubMed1998

Genomic organization and mapping of the human activin receptor type IIB (hActR-IIB) gene.

Activins, members of a family of proteins that includes transforming growth factor-beta (TGF-beta), are gonadal polypeptide hormones that stimulate secretion of follicle-stimulating hormone (FSH). During large-scale sequencing analysis of a 1.2-Mb fragment of human genomic DNA on 3p22-p21.3, we found the gene encoding activin receptor type IIB (hActR-IIB). Comparison of its reported cDNA sequence with this genomic sequence showed that the hActR-IIB gene consists of 11 exons and spans about 30 kb of genomic DNA.

Activin Receptors, Type II↗

PubMed2002

Properties of inhibin binding to betaglycan, InhBP/p120 and the activin type II receptors.

Activin-stimulated FSH synthesis and release by the pituitary gonadotrope is antagonized by gonadally derived inhibins. The two isoforms of inhibin, inhibin A and B, bind to the activin type II receptors, though at a lower affinity than the activins, but do not stimulate intracellular signaling. Theoretically, therefore, inhibins can prevent activin signaling through competitive binding if present at higher concentrations than the activins. In reality, the inhibins have been shown to antagonize activin signaling when the two ligand types are present at equimolar concentrations. These observations led to the hypothesis that inhibin binding proteins or co-receptors exist that either increase the affinity of the inhibins for the activin receptors or propagate inhibin-specific intracellular signals. Two candidate inhibin co-receptors, betaglycan and InhBP/p120, interact with activin receptors and augment inhibin antagonism of activin action. Here, we report the effect of betaglycan and InhBP/p120 on both inhibin A and inhibin B binding to the activin receptors ActRIIA and ActRIIB2. InhBP/p120 did not bind inhibin A or B when expressed alone or in combination with activin receptors, requiring a re-examination of the role of this protein in inhibin biology. Both inhibins bound the activin type II receptor, ActRIIB2. Inhibin B had a higher affinity for this receptor than inhibin A but an approximately 10-fold lower affinity than that of activin A. Inhibin A and B bound betaglycan with high affinity; however, only inhibin A binding to ActRIIB2 was significantly enhanced in the presence of betaglycan. Both inhibin isoforms showed slight but significant binding to ActRIIA, yet this binding was potentiated in the presence of betaglycan. Additionally, the complex formed between the inhibins, ActRIIA, and betaglycan was resistant to disruption by activin A, whereas activin A potently competed for inhibin binding to ActRIIB2 and betaglycan. Collectively, these data show that the inhibin isoforms have different affinities for the activin type II receptors but bind betaglycan with high affinity. A recently developed model of inhibin action proposes that inhibins form a high affinity, activin-resistant ternary complex with activin type II receptors and betaglycan, thereby providing a mechanism for inhibin antagonism of activin signaling. Importantly, the results presented here clearly show that this model does not apply equally to both forms of inhibin nor to the different activin type II receptor isoforms. Thus, it appears that the mechanisms of inhibin action may vary depending on the ligand and receptor types involved.

Activin Receptors↗

PubMed2002

Effect of adenovirus-mediated overexpression of follistatin and extracellular domain of activin receptor type II on gonadotropin secretion in vitro and in vivo.

Activins are dimeric proteins that stimulate the synthesis and secretion of pituitary FSH by interacting with two classes of receptors, type I and type II, to initiate their intracellular signaling cascade. The extracellular domain of type II activin receptor (ActRII-ECD) contains all structural determinants sufficient for high affinity ligand binding. A soluble recombinant ActRII-ECD has been reported to attenuate FSH secretion from cultured rat anterior pituitary cells in response to exogenous activin A or endogenous activin B. Follistatin is a binding protein that acts as an extracellular factor to bind and inactivate activin. We constructed adenoviral vectors able to mediate expression of follistatin 288 (AdexCAFS288) and ActRII-ECD (AdexCAECD) and tested their biological activities both in vitro and in vivo. The data show that adenovirus-mediated overexpression of either ActRII-ECD or follistatin was able to attenuate FSH secretion by cultured rat anterior pituitary cells. However, AdexCAFS288 overexpression of follistatin was more effective than adenovirus-mediated overexpression of ActRII-ECD. In vivo, a single ip injection of AdexCAFS288 induced the expression of high levels of follistatin and resulted in the suppression of serum FSH levels in castrated male rats for up to 12 d postinjection. Infection with AdexCAFS288 had no effect on LH secretion in vitro or in vivo, demonstrating its selectivity. In conclusion, the results demonstrate the effectiveness of adenovirus-mediated overexpression of follistatin and ActRII-ECD to regulate FSH secretion and the potential of using this strategy as a tool to further define the critical role of activin/inhibin/follistatin circuitry in the modulation of the reproductive system.

Activin Receptors, Type II↗