Genomes and Genes
Summary: Receptors for ACTIVINS are membrane protein kinases belonging to the family of PROTEIN-SERINE-THREONINE KINASES, thus also named activin receptor-like kinases (ALK's). Activin receptors also bind TRANSFORMING GROWTH FACTOR BETA. As those transmembrane receptors of the TGF-beta superfamily (RECEPTORS, TRANSFORMING GROWTH FACTOR BETA), ALK's consist of two different but related protein kinases, Type I and Type II. Activins initiate cellular signal transduction by first binding to the type II receptors (ACTIVIN RECEPTORS, TYPE II ) which then recruit and phosphorylate the type I receptors (ACTIVIN RECEPTORS, TYPE I ) with subsequent activation of the type I kinase activity.
- Schulte K, Jonas C, Krebs R, Roher H. Activin A and activin receptors in thyroid cancer. Thyroid. 2001;11:3-14 pubmed..Two subtypes of type I and type II activin receptors were demonstrated...
- Vallier L, Touboul T, Brown S, Cho C, Bilican B, Alexander M, et al. Signaling pathways controlling pluripotency and early cell fate decisions of human induced pluripotent stem cells. Stem Cells. 2009;27:2655-66 pubmed publisher..Together these data reveal that human iPSCs rely on mechanisms similar to human ESCs to maintain their pluripotency and to control their differentiation, showing that these pluripotent cell types are functionally equivalent. ..
- Jornvall H, Blokzijl A, ten Dijke P, Ibanez C. The orphan receptor serine/threonine kinase ALK7 signals arrest of proliferation and morphological differentiation in a neuronal cell line. J Biol Chem. 2001;276:5140-6 pubmed..These results indicate that ALK7 may participate in the control of proliferation of neuronal precursors and morphological differentiation of postmitotic neurons. ..
- Matzuk M, Kumar T, Bradley A. Different phenotypes for mice deficient in either activins or activin receptor type II. Nature. 1995;374:356-60 pubmed..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. ..
- Dewulf N, Verschueren K, Lonnoy O, Moren A, Grimsby S, Vande Spiegle K, et al. Distinct spatial and temporal expression patterns of two type I receptors for bone morphogenetic proteins during mouse embryogenesis. Endocrinology. 1995;136:2652-63 pubmed..In addition, the expression of these genes in many soft tissues suggests broader functions for BMPs in embryogenesis. ..
- Mintzer K, Lee M, Runke G, Trout J, Whitman M, Mullins M. Lost-a-fin encodes a type I BMP receptor, Alk8, acting maternally and zygotically in dorsoventral pattern formation. Development. 2001;128:859-69 pubmed..In total, our work strongly supports the role of Laf/Alk8 as a type I BMP receptor required for the specification of ventral cell fates. ..
- Brummel T, Abdollah S, Haerry T, Shimell M, Merriam J, Raftery L, et al. The Drosophila activin receptor baboon signals through dSmad2 and controls cell proliferation but not patterning during larval development. Genes Dev. 1999;13:98-111 pubmed..Our results define a novel Drosophila Activin/TGF-beta pathway that is analogous to its vertebrate counterpart and show that this pathway functions to promote cellular growth with minimal effects on patterning. ..
- Jeruss J, Sturgis C, Rademaker A, Woodruff T. Down-regulation of activin, activin receptors, and Smads in high-grade breast cancer. Cancer Res. 2003;63:3783-90 pubmed..The deregulation of this signal transduction system may be relevant to advancing oncogenic progression. ..
- Sidis Y, Fujiwara T, Leykin L, Isaacson K, Toth T, Schneyer A. Characterization of inhibin/activin subunit, activin receptor, and follistatin messenger ribonucleic acid in human and mouse oocytes: evidence for activin's paracrine signaling from granulosa cells to oocytes. Biol Reprod. 1998;59:807-12 pubmed..Taken together with previous studies, these results indicate that oocytes may be capable of responding to, but not synthesizing, activin. ..
- Yelick P, Abduljabbar T, Stashenko P. zALK-8, a novel type I serine/threonine kinase receptor, is expressed throughout early zebrafish development. Dev Dyn. 1998;211:352-61 pubmed..3 kb. zALK-8 mRNA expression correlates well with known functions of TGF-beta family members as early axial patterning and mesoderm-inducing growth factors and as potent growth and differentiation factors in craniofacial development. ..
- Yonemori K, Imamura T, Ishidou Y, Okano T, Matsunaga S, Yoshida H, et al. Bone morphogenetic protein receptors and activin receptors are highly expressed in ossified ligament tissues of patients with ossification of the posterior longitudinal ligament. Am J Pathol. 1997;150:1335-47 pubmed..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. ..
- Lebrun J, Vale W. Activin and inhibin have antagonistic effects on ligand-dependent heteromerization of the type I and type II activin receptors and human erythroid differentiation. Mol Cell Biol. 1997;17:1682-91 pubmed
- Gesualdi S, Haerry T. Distinct signaling of Drosophila Activin/TGF-beta family members. Fly (Austin). 2007;1:212-21 pubmed..The distinct signaling of dACT, DAW and MYO through BABO suggests the existence of co-receptors that modulate the canonical SMAD pathway. ..
- Heinecke K, Seher A, Schmitz W, Mueller T, Sebald W, Nickel J. Receptor oligomerization and beyond: a case study in bone morphogenetic proteins. BMC Biol. 2009;7:59 pubmed publisher..This indicates that despite prominent ligand receptor promiscuity a manifold of diverse signals might be generated in this receptor limited system. ..
- Schneider Kolsky M, Manuelpillai U, Waldron K, Dole A, Wallace E. The distribution of activin and activin receptors in gestational tissues across human pregnancy and during labour. Placenta. 2002;23:294-302 pubmedThe aim of this study was to investigate localization and content of activin beta A-subunit and activin receptors in gestational tissues throughout pregnancy and in association with term labour...
- Drummond A, Le M, Ethier J, Dyson M, Findlay J. Expression and localization of activin receptors, Smads, and beta glycan to the postnatal rat ovary. Endocrinology. 2002;143:1423-33 pubmed..The colocalization of receptors and Smads supports the notion that activin/TGF beta and BMP signaling pathways are functional in the cellular compartments of the follicle. ..
- Bernard D, Chapman S, Woodruff T. An emerging role for co-receptors in inhibin signal transduction. Mol Cell Endocrinol. 2001;180:55-62 pubmed..Several cell surface proteins that associate with inhibin have been identified recently, and these molecules may provide the clues necessary to understand how inhibin regulates reproductive function. ..
- Bauer H, Lele Z, Rauch G, Geisler R, Hammerschmidt M. The type I serine/threonine kinase receptor Alk8/Lost-a-fin is required for Bmp2b/7 signal transduction during dorsoventral patterning of the zebrafish embryo. Development. 2001;128:849-58 pubmed..Altogether, the data suggest that Alk8 acts as a Bmp2b/7 receptor upstream of Smad5. ..
- Zimmerman C, Mathews L. Activin receptors: cellular signalling by receptor serine kinases. Biochem Soc Symp. 1996;62:25-38 pubmed..We have begun to identify intracellular targets of these molecules by using the intracellular domains of both ActRIs and ActRIIs as probes in the two-hybrid system, a cloning strategy designed to detect interacting proteins in yeast. ..
- Attisano L, Carcamo J, Ventura F, Weis F, Massague J, Wrana J. Identification of human activin and TGF beta type I receptors that form heteromeric kinase complexes with type II receptors. Cell. 1993;75:671-80 pubmed..The results indicate that type I receptors are transmembrane protein kinases that associate with type II receptors to generate diverse heteromeric serine/threonine kinase complexes of different signaling capacities. ..
- Macias Silva M, Hoodless P, Tang S, Buchwald M, Wrana J. Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2. J Biol Chem. 1998;273:25628-36 pubmed..Furthermore, we show that ALK1 (TSRI), an orphan receptor that is closely related to ALK2 also mediates Smad1 signaling. Thus, ALK1 and ALK2 induce Smad1-dependent pathways and ALK2 functions to mediate BMP7 but not activin signaling. ..
- Sonoyama K, Rutatip S, Kasai T. Gene expression of activin, activin receptors, and follistatin in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2000;278:G89-97 pubmedGene expression of activin, activin receptors, and follistatin was investigated in vivo and in vitro using semiquantitative RT-PCR in intestinal epithelial cells...
- ten Dijke P, Ichijo H, Franzen P, Schulz P, Saras J, Toyoshima H, et al. Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. Oncogene. 1993;8:2879-87 pubmed..The ALKs have approximately 40% sequence identity to activin receptors type II and IIB, transforming growth factor-beta (TGF-beta) type II receptor and Daf-1 in the kinase domains...
- Ben Haim N, Lu C, Guzman Ayala M, Pescatore L, Mesnard D, Bischofberger M, et al. The nodal precursor acting via activin receptors induces mesoderm by maintaining a source of its convertases and BMP4. Dev Cell. 2006;11:313-23 pubmed..Surprisingly, however, the Nodal precursor binds and activates activin receptors to maintain expression of Furin, PACE4, and Bmp4 in extraembryonic ectoderm at a distance from the Nodal ..
- Izadyar F, Dijkstra G, van Tol H, van den Eijnden van Raaij A, van den Hurk R, Colenbrander B, et al. Immunohistochemical localization and mRNA expression of activin, inhibin, follistatin, and activin receptor in bovine cumulus-oocyte complexes during in vitro maturation. Mol Reprod Dev. 1998;49:186-95 pubmed..This action may be modulated by inhibin and/or follistatin. ..
- Ten Dijke P, Hill C. New insights into TGF-beta-Smad signalling. Trends Biochem Sci. 2004;29:265-73 pubmed
- Feijen A, Goumans M, van den Eijnden van Raaij A. Expression of activin subunits, activin receptors and follistatin in postimplantation mouse embryos suggests specific developmental functions for different activins. Development. 1994;120:3621-37 pubmed..encoding the inhibin/activin subunits (alpha, beta A, beta B), the activin-binding protein follistatin and activin receptors (IIA, IIB) in mouse embryos during postimplantation development. From 6.5- to 9.5-days post coitum (p.c...
- Jones R, Salamonsen L, Zhao Y, Ethier J, Drummond A, Findlay J. Expression of activin receptors, follistatin and betaglycan by human endometrial stromal cells; consistent with a role for activins during decidualization. Mol Hum Reprod. 2002;8:363-74 pubmed..We examined the expression of activin receptors (ActRs) by semi-quantitative and real-time RT-PCR...
- Lewis K, Gray P, Blount A, MacConell L, Wiater E, Bilezikjian L, et al. Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. Nature. 2000;404:411-4 pubmed..Inhibins also bind type II activin receptors but do not recruit ALK4, providing a competitive model for the antagonism of activin by inhibin...
- Bernard D, Chapman S, Woodruff T. Inhibin binding protein (InhBP/p120), betaglycan, and the continuing search for the inhibin receptor. Mol Endocrinol. 2002;16:207-12 pubmed..Characterization of these proteins, coupled with ongoing investigations of betaglycan and InhBP/p120, will lead to a clearer understanding of mechanisms of inhibin action. ..
- Oh S, Seki T, Goss K, Imamura T, Yi Y, Donahoe P, et al. Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A. 2000;97:2626-31 pubmed..Taken together, our results suggest that the balance between the ALK1 and ALK5 signaling pathways in endothelial cells plays a crucial role in determining vascular endothelial properties during angiogenesis. ..
- Tsuchida K, Nakatani M, Uezumi A, Murakami T, Cui X. Signal transduction pathway through activin receptors as a therapeutic target of musculoskeletal diseases and cancer. Endocr J. 2008;55:11-21 pubmed..In this review, we discuss the role of signaling through activin receptors as therapeutic targets of intractable neuromuscular diseases, endocrine disorders and cancers.
- Attisano L, Wrana J, Cheifetz S, Massague J. Novel activin receptors: distinct genes and alternative mRNA splicing generate a repertoire of serine/threonine kinase receptors. Cell. 1992;68:97-108 pubmed..All isoforms bind inhibin A with low affinity. Thus, the repertoire of activin receptors includes species that differ in ligand binding affinity, cytoplasmic domain structure, or both...
- Muttukrishna S, Bearfield C, Johns J, Jauniaux E. Inhibin, activin, follistatin, activin receptors and beta-glycan gene expression in the villous tissue of miscarriage patients. Mol Hum Reprod. 2004;10:793-8 pubmed..was to quantify relative expression of inhibin alpha, inhibin/activin betaA, betaB, betaC, follistatin, activin receptors and beta-glycan genes and content of inhibin A, activin A and follistatin protein in villous tissue of first ..
- Chen C, Shen M. Two modes by which Lefty proteins inhibit nodal signaling. Curr Biol. 2004;14:618-24 pubmed..Genetic and biochemical analyses have shown that Nodal signaling is mediated by activin receptors but also requires EGF-CFC coreceptors, such as mammalian Cripto or Cryptic...
- ten Dijke P, Yamashita H, Ichijo H, Franzen P, Laiho M, Miyazono K, et al. Characterization of type I receptors for transforming growth factor-beta and activin. Science. 1994;264:101-4 pubmed
- Fukui A, Komazaki S, Miyoshi O, Asashima M. Immunocytochemical study of activin type IB receptor (XALK4) in Xenopus oocytes. Dev Growth Differ. 2003;45:113-9 pubmed..Purified antibody against the intracellular domain also recognized the mitochondrial cloud. Immunoelectron microscopy localized XALK4 on the endoplasmic reticulum of the mitochondrial cloud, although not on mitochondria. ..
- Graham H, Peng C. Activin receptor-like kinases: structure, function and clinical implications. Endocr Metab Immune Disord Drug Targets. 2006;6:45-58 pubmed..Some ALKs have been implicated in several disorders, including tumorigenesis, hemorrhagic telangiectasia (HHT), immune and renal diseases, and skeletal malfunctions, suggesting that these receptors can be used as drug targets. ..
- Gray P, Bilezikjian L, Vale W. Antagonism of activin by inhibin and inhibin receptors: a functional role for betaglycan-glycan. Mol Cell Endocrinol. 2001;180:47-53 pubmed..Here we summarize recent advances in understanding inhibin's mode of action focusing on our recent identification of betaglycan-glycan as an inhibin co-receptor capable of mediating inhibin action. ..
- Nakamura M, Matzuk M, Gerstmayer B, Bosio A, Lauster R, Miyachi Y, et al. Control of pelage hair follicle development and cycling by complex interactions between follistatin and activin. FASEB J. 2003;17:497-9 pubmed..These observations suggest that follistatin and activin interaction plays an important role in both HF development and cycling, possibly in part by regulating expression of BMP-2 and its antagonist. ..
- Young J, McNeilly A. Inhibin removes the inhibitory effects of activin on steroid enzyme expression and androgen production by normal ovarian thecal cells. J Mol Endocrinol. 2012;48:49-60 pubmed publisher..Inhibin and other blockers of activin action reversed this effect, supporting the concept that endogenous thecal activin modulates androgen production in theca cells. ..
- Ciarmela P, Bloise E, Gray P, Carrarelli P, Islam M, De Pascalis F, et al. Activin-A and myostatin response and steroid regulation in human myometrium: disruption of their signalling in uterine fibroid. J Clin Endocrinol Metab. 2011;96:755-65 pubmed publisher..Cripto mRNA was expressed only in HL. A and M act on human HM and are regulated by steroids. In HL there is an increase of A, M, FLRG, and Cripto expression. ..
- Geng H, Lan R, Wang G, Siddiqi A, Naski M, Brooks A, et al. Inhibition of autoregulated TGFbeta signaling simultaneously enhances proliferation and differentiation of kidney epithelium and promotes repair following renal ischemia. Am J Pathol. 2009;174:1291-308 pubmed publisher..To that end, TGFbeta signaling is redundant and maladaptive during tubule repair by epithelial regeneration. ..
- Urness L, Sorensen L, Li D. Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet. 2000;26:328-31 pubmed..The early loss of anatomical, molecular and functional distinctions between arteries and veins indicates that Acvrl1 is required for developing distinct arterial and venous vascular beds. ..
- Chattopadhyay N, T Felt Hansen J, Godbole M, Brown E. Transforming growth factor beta receptor family ligands inhibit hepatocyte growth factor synthesis and secretion from astrocytoma cells. Brain Res Mol Brain Res. 2004;121:146-50 pubmed..Because interfering with TbetaR signaling might nullify the beneficial inhibition of HGF secretion, activin-A should instead be considered for combination glioma therapy. ..
- Barnett J, Desgrosellier J. Early events in valvulogenesis: a signaling perspective. Birth Defects Res C Embryo Today. 2003;69:58-72 pubmed..This review will focus on molecules and emerging pathways that guide early events in valvulogenesis. ..
- Danila D, Zhang X, Zhou Y, Dickersin G, Fletcher J, Hedley Whyte E, et al. A human pituitary tumor-derived folliculostellate cell line. J Clin Endocrinol Metab. 2000;85:1180-7 pubmed..Therefore, this human cell line provides a useful model for studying the regulation of cell growth and cytokine production by factors endogenously produced in pituitary folliculostellate cells. ..
- Peng C, Ohno T, Khorasheh S, Leung P. Activin and follistatin as local regulators in the human ovary. Biol Signals. 1996;5:81-9 pubmed..The effect of activin is most likely mediated through specific receptors as mRNAs encoding several forms of activin receptors, namely ActR-I, ActR-IB, ActR-II and ActR-IIB are found in the preovulatory follicles as well as in cultured ..
- Abe Y, Minegishi T, Leung P. Activin receptor signaling. Growth Factors. 2004;22:105-10 pubmed..The presence of many mechanisms for regulation shows its importance to normal physiology. Here, we review the latest advances in activin signal transduction. ..
- Xu J, McKeehan K, Matsuzaki K, McKeehan W. Inhibin antagonizes inhibition of liver cell growth by activin by a dominant-negative mechanism. J Biol Chem. 1995;270:6308-13 pubmed..The results suggest that inhibin may be a natural antagonist of assembly of the heterodimeric activin receptor complex through a dominant-negative mechanism. ..
- Pernasetti F, Vasilyev V, Rosenberg S, Bailey J, Huang H, Miller W, et al. Cell-specific transcriptional regulation of follicle-stimulating hormone-beta by activin and gonadotropin-releasing hormone in the LbetaT2 pituitary gonadotrope cell model. Endocrinology. 2001;142:2284-95 pubmed..exhibit the characteristics of fully differentiated gonadotropes, including the expression of LH, FSH, GnRH receptor, and components of the activin/follistatin system, as well as display the appropriate responses to activin and GNRH: ..
- Miller M, Lambert Messerlian G, Eklund E, Heath N, Donahue J, Stopa E. Expression of inhibin/activin proteins and receptors in the human hypothalamus and basal forebrain. J Neuroendocrinol. 2012;24:962-72 pubmed publisher..These studies show for the first time that the inhibin/activin protein subunits and receptors can be co-localised in the human brain, implicating potential, diverse neural functions. ..