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At least 19 recordsLinked to original sources
PubMed1996

Distinct localization of two serine-threonine kinase receptors for activin and TGF-beta in the rat brain and down-regulation of type I activin receptor during peripheral nerve regeneration.

The localizations of serine-threonine kinase receptor mRNA for the novel type I TGF-beta and/or activin receptor named B1 (rat), ALK-4 (mouse) or ActR-IB (human) were demonstrated by in situ hybridization. As the putative ligand for this receptor in the brain has not yet been clearly determined, we compared its localization to type II activin receptor (ActR-II) which is the counterpart of the type I activin receptor. B1 mRNA was widely observed in neuronal cells throughout the brain, and especially strong positive signals were found in the cerebral cortex, olfactory tubercle, and hippocampus. The localization of B1 mRNA coincided well with that of ActR-II. This strongly suggests that B1 (ALK-4/ActR-IB) could be the type I activin receptor, as type I and type II activin receptor were supposed to form a receptor complex. In addition, we examined the localization of type II TGF-beta receptor (TbetaRII) mRNA which is an essential counterpart of the type I TGF-beta receptors for TGF-beta signaling. TbetaRII mRNA was expressed mainly in non-neuronal cells such as choroid plexus. In addition, TbetaRII mRNA expression was also found in a minor population of neuronal cells. TbetaRII mRNA-positive neurons were observed in the reticular thalamus, laterodorsal tegmental nucleus, pedunculopontine tegmental nucleus and the ventral tegmental nucleus. The localization of TbetaRII was markedly different from that of activin receptors in the rat brain. Since TGF-betas and activins are known as growth factors and/or survival factors, we examined changes in levels of B1 and TbetaRII mRNA expression during peripheral nerve regeneration. Expression of B1 mRNA in the axotomized hypoglossal motoneurons was substantially decreased from day 3 after axotomy and this decrease was significant until postoperative day 28, whereas no TbetaRII signal was observed in hypoglossal nucleus prior or after axotomy. This transient down-regulation of B1 mRNA expression suggests that activin signaling is somehow suppressed during peripheral nerve regeneration.

Activin Receptors↗
PubMed2000

Identification of a binding site on the type II activin receptor for activin and inhibin.

Type II activin receptors (ActRII and ActRIIB) are single-transmembrane domain serine/threonine kinase receptors that bind activin to initiate the signaling and cellular responses triggered by this hormone. Inhibin also binds type II activin receptors and antagonizes many activin effects. Here we describe alanine scanning mutagenesis of the ActRII extracellular domain. We identify a cluster of three hydrophobic residues (Phe(42), Trp(60), and Phe(83)) that, when individually mutated to alanine in the context of the full-length receptor, cause the disruption of activin and inhibin binding to ActRII. Each of the alanine-substituted ActRII mutants retaining activin binding maintains the ability to form cross-linked complexes with activin and supports activin cross-linking to the type I activin receptor ALK4. Unlike wild-type ActRII, the three mutants unable to bind activin do not cause an increase in activin signaling when transiently expressed in a corticotroph cell line. Together, our results implicate these residues in forming a critical binding surface on ActRII required for functional interactions with both activin and inhibin. This first identification of a transforming growth factor-beta family member binding site may provide a general basis for characterizing binding sites for other members of the superfamily.

Activin Receptors↗
PubMed1999

Impaired differentiation of endocrine and exocrine cells of the pancreas in transgenic mouse expressing the truncated type II activin receptor.

Activin A is expressed in endocrine precursor cells of the fetal pancreatic anlage. To determine the physiological significance of activins in the pancreas, a transgenic mouse line expressing the truncated type II activin receptor under the control of beta-actin promoter was developed. Histological analyses of the pancreas revealed that the pancreatic islets of the transgenic mouse were small in size and were located mainly along the pancreatic ducts. Immunoreactive insulin was detected in islets, some acinar cells, and in some epithelial cells in the duct. In addition, there were abnormal endocrine cells outside the islets. The shape and the size of the endocrine cells varied and some of them were larger than islets. These cells expressed immunoreactive insulin and glucagon. In the exocrine portion, there were morphologically abnormal exocrine cells, which did not form a typical acinar structure. The cells lacked spatial polarity characteristics of acinar cells but expressed immunoreactive amylase, which was distributed diffusely in the cytoplasm. Plasma glucose concentration was normal in the transgenic mouse before and after the administration of glucose. The insulin content of the pancreas in transgenic and normal mice was nearly identical. These results suggest that activins or related ligands regulate the differentiation of the pancreatic endocrine and exocrine cells.

Activin Receptors, Type II↗
PubMed1995

Inactivation of activin-dependent transcription by kinase-deficient activin receptors.

Activin, a member of the transforming growth factor-beta superfamily, binds to two classes of cell surface receptors. These receptors, designated type I and type II, are structurally related members of transmembrane serine kinase superfamily. Antibodies specific for either type I or type II activin receptor can coprecipitate complexes containing both affinity-labeled receptors from activin-responsive cells. Two type I receptors show cell-specific expression and associate with the ligand-binding, type II receptors. To investigate the roles of the cytoplasmic receptor domains in signaling through a heteromeric ligand receptor complex, we have made kinase-deficient activin receptors and correlated their losses in kinase activity with inhibitory effects on an activin-dependent transcriptional response in activin-responsive cell lines. Wild-type activin type II receptors phosphorylate activin type I receptors in transfected COS cells. In contrast, kinase-deficient activin type II receptors fail to phosphorylate type I receptors in transfected COS cells and act as dominant negative mutants to block activin-induced transcriptional activity in both Chinese hamster ovary and K562 (human erythroleukemia) cells. Kinase-deficient activin type IB receptors also block activin-induced transcriptional activity in both Chinese hamster ovary and K562 cells, whereas kinase-deficient activin type I receptors have no effect in either cell line. These results indicate that kinase activities of both type II and type I receptors are required for activin signaling, and that the two type I receptors, which are expressed in a tissue-specific manner, are functionally distinct.

Activin Receptors↗
PubMed1993

Molecular and functional characterization of activin receptors.

Activins are multifunctional proteins with effects on a broad spectrum of cells and tissues. They are structurally related to a large family of growth and differentiation factors that includes the inhibins, the transforming growth factors b (TGFb), the bone morphogenetic proteins (BMP), Mullerian inhibitory substance, and a number of gene products that control the development of Drosophila and Xenopus. Although the cellular signaling mechanisms of these factors remain unclear, cDNAs encoding cell surface receptors for activin have been cloned. Those receptors are transmembrane serine kinases, suggesting a novel form of signaling. Overexpression of activin receptors in Xenopus embryos indicates that these molecules are functionally involved in the transmission of the activin signal.

Activin Receptors↗
PubMed1993

Identification of a Drosophila activin receptor.

Activins are cytokines of the transforming growth factor beta superfamily that control various events during vertebrate embryo development and cell differentiation in the adult, and act through transmembrane receptors that contain a cytoplasmic protein-serine/threonine kinase domain. We describe the identification, deduced primary structure, and expression pattern of Atr-II, a receptor serine/threonine kinase found in Drosophila. With the exception of the spacing of 10 cysteine residues, the extracellular domain of Atr-II is very dissimilar from those of vertebrate activin receptors, yet it binds activin with high affinity and specificity. The kinase domain sequence of Atr-II is 60% identical to those of activin receptors from vertebrates, suggesting similarities in their signaling mechanisms. Maternal Atr-II transcript and its product are abundant in the oocyte. During development, the highest levels of Atr-II transcript and protein are observed in the mesoderm and gut. The possible role of an activin signaling system in Drosophila development is discussed.

Activin Receptors↗
PubMed2004

Characterization of the bone morphogenetic protein (BMP) system in human pulmonary arterial smooth muscle cells isolated from a sporadic case of primary pulmonary hypertension: roles of BMP type IB receptor (activin receptor-like kinase-6) in the mitotic action.

The functional involvement of bone morphogenetic protein (BMP) system in primary pulmonary hypertension (PPH) remains unclear. Here we demonstrate a crucial role of the BMP type IB receptor, activin receptor-like kinase (ALK)-6 for pulmonary arterial smooth muscle cell (pphPASMC) mitosis isolated from a sporadic PPH patient bearing no mutations in BMPR2 gene. A striking increase in the levels of ALK-6 mRNA was revealed in pphPASMC compared with control PASMCs, in which ALK-6 transcripts were hardly detectable. BMP-2 and -7 stimulated the mitosis of pphPASMCs, which was opposite to their suppressive effects on the mitosis of the control PASMCs. BMP-4 and -6 and activin inhibited pphPASMC mitosis, whereas these did not affect control PASMCs. The presence of BMP signaling machinery in pphPASMCs was elucidated based on the analysis on Id-1 transcription and Smad-reporter genes. Overexpression of a dominant-negative ALK-6 construct revealed that ALK-6 plays a key role in the mitosis as well as intracellular BMP signaling of pphPASMCs. Gene silencing of ALK-6 using small interfering RNA also reduced DNA synthesis as well as Id-1 transcription in pphPASMCs regardless of BMP-2 stimulation. Although Id-1 response was not stimulated by BMP-2 in control PASMCs, the gene delivery of wild-type ALK-6 caused significant increase in the Id-1 transcripts in response to BMP-2. Additionally, inhibitors of ERK and p38 MAPK pathways suppressed pphPASMC mitosis induced by BMP-2, implying that the mitotic action is in part MAPK dependent. Thus, the BMP system is strongly involved in pphPASMC mitosis through ALK-6, which possibly leads to activation of Smad and MAPK, resulting in the progression of vascular remodeling of pulmonary arteries in PPH.

Adolescent↗
PubMed1992

A carboxyl-terminal truncated version of the activin receptor mediates activin signals in early Xenopus embryos.

The function of a carboxyl-terminal truncated version of the Xenopus activin receptor, encoded by a previously isolated gene XSTK2, was investigated in early embryos. The transcript corresponding to the truncated receptor gene was detected throughout embryonic development although the temporal expression pattern was different from that of an intact receptor. Injection of XSTK2 mRNA into early embryos resulted in the formation of a duplicated body axis. Mesoderm induction as evaluated by the activation of the alpha-actin gene in presumptive ectoderm (animal cap) treated with exogenous activin was significantly enhanced by the injection of XSTK2 mRNA. These results suggest that the truncated receptor is capable of transmitting the activin signal to the same extent as the native receptor.

Actins↗
PubMed2004

Human retroviral gag- and gag-pol-like proteins interact with the transforming growth factor-beta receptor activin receptor-like kinase 1.

Mutations in activin receptor-like kinase 1 (ALK1), a transforming growth factor (TGF)-beta type I receptor, lead to the vascular disorder hereditary hemorrhagic telangiectasia caused by abnormal vascular remodeling. The underlying molecular cause of this disease is not well understood. Identifying binding partners for ALK1 will help to understand its cellular function. Using the two-hybrid system, we identified an ALK1-binding protein encoded by an ancient retroviral/retrotransposon element integrated as a single copy gene known as PEG10 on human chromosome 7q21. PEG10 contains two overlapping reading frames from which two proteins, PEG10-RF1 and PEG10-RF1/2, are translated by a typical retroviral -1 ribosomal frameshift mechanism. Reverse transcription-PCR and Northern blot analysis showed a broad range of PEG10 expression in different tissues and cell types, i.e. human placenta, brain, kidney, endothelial cells, lymphoblasts, and HepG2 and HEK293 cells. However, endogenous PEG10-RF1 and PEG10-RF1/2 proteins were only detected in HepG2 and HEK293 cells. PEG10-RF1, which is the major PEG10 protein product, represents a gag-like protein, and PEG10-RF1/2 represents a gag-pol-like protein. PEG10-RF1 also interacts with different members of TGF-beta superfamily type I and II receptors. PEG10-RF1 binding to ALK1 is mediated by a 200-amino acid domain with no recognized motif. PEG10-RF1 inhibits ALK1 as well as ALK5 signaling. Co-expression of ALK1 and PEG10-RF1 in different cell types induced morphological changes reminiscent of neuronal cells or sprouting cells. This is the first report of a human retroviral-like protein interacting with members of the TGF-beta receptor family.

Activin Receptors, Type I↗
PubMed2003

Growth differentiation factor-9 signaling is mediated by the type I receptor, activin receptor-like kinase 5.

Growth differentiation factor-9 (GDF-9) is an oocyte-derived growth factor and a member of the TGF-beta superfamily that includes TGF-beta, activin, and bone morphogenetic proteins (BMPs). GDF-9 is indispensable for the development of ovarian follicles from the primary stage, and treatment with GDF-9 enhances the progression of early follicles into small preantral follicles. Similar to other TGF-beta family ligands, GDF-9 likely initiates signaling mediated by type I and type II receptors with serine/threonine kinase activity, followed by the phosphorylation of intracellular transcription factors named Smads. We have shown previously that GDF-9 interacts with the BMP type II receptor (BMPRII) in granulosa cells, but the type I receptor involved is unknown. Using P19 cells, we now report that GDF-9 treatment stimulated the CAGA-luciferase reporter known to be responsive to TGF-beta mediated by the type I receptor, activin receptor-like kinase (ALK)5. In contrast, GDF-9 did not stimulate BMP-responsive reporters. In addition, treatment with GDF-9 induced the phosphorylation of Smad2 and Smad3 in P19 cells, and the stimulatory effect of GDF-9 on the CAGA-luciferase reporter was blocked by the inhibitory Smad7, but not Smad6. We further reconstructed the GDF-9 signaling pathway using Cos7 cells that are not responsive to GDF-9. After overexpression of ALK5, with or without exogenous Smad3, the Cos7 cells gained GDF-9 responsiveness based on the CAGA-luciferase reporter assay. The roles of ALK5 and downstream pathway genes in mediating GDF-9 actions were further tested in ovarian cells. In cultured rat granulosa cells from early antral follicles, treatment with GDF-9 stimulated the CAGA-luciferase reporter activity and induced the phosphorylation of Smad3. Furthermore, transfection with small interfering RNA for ALK5 or overexpression of the inhibitory Smad7 resulted in dose-dependent suppression of GDF-9 actions. In conclusion, although GDF-9 binds to the BMP-activated type II receptor, its downstream actions are mediated by the type I receptor, ALK5, and the Smad2 and Smad3 proteins. Because ALK5 is a known receptor for TGF-beta, diverse members of the TGF-beta family of ligands appear to interact with a limited number of receptors in a combinatorial manner to activate two downstream Smad pathways.

Activin Receptors↗
PubMed1995

Expression of activin receptors type I and II only partially overlaps in the nervous system.

In situ hybridization was used to localize mRNA encoding two cooperative serine/threonine kinase receptors. Activin receptor IIA mRNA in the adult rat brain is highly expressed in the dentate gyrus, in the pyramidal neurones of CA3 and CA1, in the entorhinal cortex, in the cortical amygdaloid nucleus and in the amygdalohippocampal area. In the E16 rat embryo, labelling was found in the dorsal root ganglion neurones and in the spinal cord. Activin type I receptor (ALK-2/R-1) labelling was also localized to the hippocampal formation but with an even distribution over the granular cells of the dentate gyrus, the CA3 and CA1 pyramidal neurones, while no labelling was found in the entorhinal or amygdaloid areas. In the E16 rat no neuronal labelling was found. The incomplete overlap of these two expression patterns suggests that these receptors may locally have other partners for forming signalling receptor complexes.

Activin Receptors↗
PubMed1997

Bone morphogenetic protein receptors and activin receptors are highly expressed in ossified ligament tissues of patients with ossification of the posterior longitudinal ligament.

Ossification of the posterior longitudinal ligament (OPLL) is a pathological ossification in the spinal ligament, with formation of ectopic bone mainly through endochondral ossification. Bone morphogenetic proteins (BMPs) and activins are multifunctional proteins that belong to the transforming growth factor-beta superfamily and that have been implicated in the formation of new bone and cartilage. BMPs and activins signal via type I and type II receptors for BMPs (BMPRs) and activins (ActRs), respectively. OP-1/BMP-7 binds to BMPR-II and ActR-II and forms complexes with BMPR-IA and -IB and ActR-I. We studied the expression of BMPR-IA, -IB, and -II, ActR-I, ActR-II, and OP-1/BMP-7 by immunohistochemistry in ossified ligament tissues of patients with OPLL and control ligament tissues from patients with cervical disc herniation. The expression of BMPRs and ActRs was elevated in OPLL compared with controls. Expressions of BMPR-IA, -IB, and -II were observed not only in chondrocytes at the fibrocartilage tissue around the calcified zone but also in fibroblast-like spindle cells at the nonossified ligament. ActR-I and -II were found co-localized in the hypertrophic chondrocytes near the calcified zone and in the ossified tissue. OP-1/BMP-7 was expressed in chondrocytes near the calcified zone. In the control cases, the BMPRs and ActRs were only weakly expressed in the fibrocartilage tissue at the site of ligament attachments to bone and OP-1/BMP-7 was not detected. Enhanced expression of BMPRs at the nonossified ligament in OPLL patients suggests that these cells have a greater potential to differentiate into osteogenic cells than ligament cells from non-OPLL patients. The high expression of BMPRs and ActRs in the ectopic ossified ligament suggests that BMPs and activin may be tightly involved in the pathological ossification process of OPLL.

Activin Receptors↗
PubMed2001

Male reproductive phenotypes in double mutant mice lacking both FSHbeta and activin receptor IIA.

Activins are known to signal through two serine/threonine kinase type II receptors. Activin receptor IIA is widely expressed in the male reproductive axis, including the pituitary and testis. Our previous studies using gene knockout mice have confirmed the essential in vivo role of activin receptor IIA in FSH homeostasis. Activin receptor IIA-null male mice are fertile, have suppressed pituitary and serum FSH levels, and demonstrate a decrease in testis size as a result of reduced Sertoli cells and germ cells. Similarly, FSHbeta null male mice are fertile despite reduced testis size and Sertoli cell number. To define the direct roles of activin receptor IIA signaling locally in the testis, independent of its effects on FSH homeostasis, we generated double mutant mice lacking both activin receptor IIA and FSH by a genetic intercross and analyzed the male reproductive phenotypes. The double mutant male mice lacking both FSH and activin receptor IIA are fertile, demonstrate no significant reduction in testis size, and produce small litters compared with mice lacking either FSH or activin receptor IIA alone. Histological analyses of the testes from double mutant mice revealed the presence of normal stages of spermatogenesis. However, there was a significant reduction in the epididymal sperm number compared with that of the individual mutants. Northern blot analyses of total RNA from testes of double mutants did not reveal transcriptional up-regulation of activin receptor IIB, the other activin type II receptor. Although RNA expression profiles of many testis cell-specific markers are unaltered, stereological analysis of the testes from double mutants indicates that there was a reduction in type A and I spermatogonial number compared with that observed in individual mutants. Our results provide in vivo genetic evidence to demonstrate that activin receptor IIA signaling plays an important local role within the testis, independent of its actions via FSH homeostasis in the pituitary.

Activin Receptors, Type II↗
PubMed1998

Hypoplasia of pancreatic islets in transgenic mice expressing activin receptor mutants.

Activin, a member of the TGF-beta superfamily, regulates the growth and differentiation of a variety of cell types. Based on the expression of activin in pancreatic rudiments of rat embryos and stimulation of insulin secretion from adult rat pancreatic islets by activin, activin is implicated in the development and function of islets. To examine the significance of activin signaling in the fetal and postnatal development of islets, transgenic mice expressing a dominant negative form of activin receptor (dn-ActR) or a constitutively active form of activin receptor (ActR-T206D) in islets were generated together with the transgenic mice expressing intact activin receptor (intact ActR) as a negative control. Transgenic mice with both dn-ActR and ActR-T206D showed lower survival rates, smaller islet area, and lower insulin content in the whole pancreas with impaired glucose tolerance when compared with transgenic mice with intact ActR or littermates, but they showed the same alpha cell/beta cell ratios as their littermates. In addition to islet hypoplasia, the insulin response to glucose was severely impaired in dn-ActR transgenic mice. It is suggested that a precisely regulated intensity of activin signaling is necessary for the normal development of islets at the stage before differentiation into alpha and beta cells, and that activin plays a role in the postnatal functional maturation of islet beta cells.

Activin Receptors↗
PubMed2001

Age-dependent activin receptor expression pinpoints activin A as a physiological regulator of rat Sertoli cell proliferation.

It is currently believed that the fertility level of the adult mammalian testis is related to the total number of Sertoli cells, which is established in the early prepubertal life. We have previously reported that, in an in-vitro system, terminal Sertoli cell proliferation is sustained by activin A in concert with FSH. In this paper, we have addressed the question of whether this activin A effect correlates with activin receptor II (ActRII) expression pattern during early post-natal testis development. We first determined the precise developmental interval of activin proliferative effect on Sertoli cells in vitro and then analysed the expression of ActRII in purified testicular cell populations by Northern blot and in-situ hybridization. While the 3 kb ActRII isoform was widely expressed at different ages and in several testicular cells, including Sertoli cells, germ cells and myoid cells, the canonical 6 kb ActRII isoform was specifically and transiently expressed at a high rate in Sertoli cells at 7-9 days after birth, the time when these cells respond to activin A in vitro. In the light of these results, we conclude that activin A regulates terminal Sertoli cell proliferation in the rat testis and that this effect is mediated by the 6 kb isoform of ActRII.

Activin Receptors, Type II↗
PubMed1999

Activin and inhibin binding to the soluble extracellular domain of activin receptor II.

Activins and inhibins belong to the transforming growth factor-beta-like superfamily of growth and differentiation factors that exert pleiotropic effects in many target tissues. Heteromeric association of activin with two structurally related receptor serine/threonine kinases, activin receptor types I and II, initiates downstream signaling events. The extracellular domain of type II mouse activin receptor (ActRII ECD) was expressed in the baculovirus system, purified in three steps by lectin affinity, anion exchange, and reverse phase chromatography, and further characterized by mass spectrometry. The reduction in the apparent size of the purified ActRII ECD on SDS-PAGE after treatment with glycosidases provided evidence for N- and O-linked oligosaccharides. Specific receptor/ligand complexes of [125I] activin A to ActRII ECD or [125I]ActRII ECD to activin A were analyzed by cross-linking and immunoprecipitation. Two major radiolabeled bands were observed on SDS-PAGE with mobilities consistent with the expected size of ActRII ECD/betaA or ActRII ECD/betaAbetaA. When inhibin A was cross-linked to [125I]ActRII ECD, a slower migrating complex corresponding to ActRII ECD/betaAalpha was also observed. The apparent dissociation constant (Kd) for activin A binding to ActRII ECD was 2-7 nM. This Kd value is approximately an order of magnitude greater than that of the full-length membrane-associated type II receptor. Treatment of cultured rat anterior pituitary cells with ActRII ECD attenuated FSH secretion in response to exogenous activin A or endogenous activin B. These data indicate that the soluble ActRII ECD has structural determinants that are sufficient for high affinity ligand binding.

Activin Receptors↗
PubMed1994

Expression of type II activin receptor genes during differentiation of human K562 cells and cDNA cloning of the human type IIB activin receptor.

Recent studies have indicated that activin A/erythroid differentiation factor is a physiologic hematopoietic growth and differentiation factor mainly for cells of the erythroid lineage. We studied the expression of the two type II activin receptor mRNAs during the differentiation of K562 erythroleukemic cells, which are known to be induced toward the erythroid lineage in response to activin or toward the megakaryoblastic lineage by phorbol myristate acetate (PMA). The cDNA of the human activin receptor type IIB (hActR-IIB) was cloned and sequenced from two RNA sources, the K562 cells and the human fetal brain, which is, of the tissues screened by Northern blot analysis, the most abundant source of ActR-IIB RNA. The cDNA encodes a predicted 512 amino acid protein containing an extracellular ligand binding domain, a hydrophobic transmembrane domain, and an intracellular serine/threonine kinase domain. The amino acid sequence is 99.2% and 98.4% homologous in the coding region to the previously described mouse and rat ActR-IIB2s, respectively, and 69% identical to the other human activin serine/threonine kinase receptor, hActR-II. The alternative splicing events in the juxtamembrane region previously reported for the respective mouse receptor were not observed during the processing of K562 cell and human fetal brain RNA. Northern analysis showed that the 10- and 2.5-kb transcripts of hActR-IIB are more abundantly expressed than the 6.0- and 3.0-kb transcripts of hActR-II in K562 cells. No changes in the steady-state levels of hActR-II and IIB mRNAs were detected upon differentiation of K562 cells by activin A or by PMA. Similarly, the receptor mRNA levels remained constant in HL-60 cells induced to either monocyte/macrophage or granulocyte-like cells by PMA or dimethyl sulfoxide, respectively. Thus, the mRNA expression levels of both receptors apparently do not correlate with the differentiation status of these cells.

Activin Receptors↗
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↗