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Wylie Vale - One of the best experts on this subject based on the ideXlab platform.
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identification of a binding site on the type ii Activin Receptor for Activin and inhibin
Journal of Biological Chemistry, 2000Co-Authors: Peter C Gray, Cynthia J. Donaldson, Jason Greenwald, Senyon Choe, Amy L Blount, Koichi S Kunitake, Wylie ValeAbstract:Abstract 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 (Phe42, Trp60, and Phe83) 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-β family member binding site may provide a general basis for characterizing binding sites for other members of the superfamily.
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Activin and Inhibin Binding to the Soluble Extracellular Domain of Activin Receptor II
Endocrinology, 1999Co-Authors: Cynthia J. Donaldson, Joan Vaughan, A. Corrigan, Wolfgang H. Fischer, Wylie ValeAbstract:Activins and inhibins belong to the transforming growth factor-β-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 expect...
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Roles of Pathway-Specific and Inhibitory Smads in Activin Receptor Signaling
Molecular Endocrinology, 1999Co-Authors: Jean-jacques Lebrun, Kazuaki Takabe, Yan Chen, Wylie ValeAbstract:Activins and other members of the transforming growth factor-β-like superfamily of growth factors transduce their signals by interacting with two types of Receptor serine/threonine kinases. The Smad proteins, a new family of intracellular mediators are involved in the signaling pathways of these Receptors, but the initial stages of their activation as well as their specific functions remain to be defined. We report here that the pathway-specific Smad2 and 3 can form a complex with the Activin Receptor in a ligand-dependent manner. This complex formation is rapid but also transient. Indeed, soon after their association with the Activin Receptor, Smad2 and Smad3 are released into the cytoplasm where they interact with the common partner Smad4. These Smad complexes then mediate Activin-induced transcription. Finally, we show that the inhibitory Smad7 can prevent the association of the two pathway-specific Smads with the Activin Receptor complex, thereby blocking the Activin signal.
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three finger toxin fold for the extracellular ligand binding domain of the type ii Activin Receptor serine kinase
Nature Structural & Molecular Biology, 1999Co-Authors: Wylie Vale, Wolfgang H. Fischer, Jason Greenwald, Senyon ChoeAbstract:Three-finger toxin fold for the extracellular ligand-binding domain of the type II Activin Receptor serine kinase.
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hybridization histochemical localization of Activin Receptor subtypes in rat brain pituitary ovary and testis
Endocrinology, 1994Co-Authors: Vicky A Cameron, Lawrence S. Mathews, E Nishimura, Kathy A Lewis, P E Sawchenko, Wylie ValeAbstract:We have studied the distribution of Activin Receptor gene expression in the brain, pituitary, ovary, and testis of the adult rat by in situ hybridization, using probes complementary to the mRNAs encoding the mouse Activin Receptor subtypes II and IIB (ActRII and ActRIIB). Throughout the brain, ActRII mRNA expression was stronger than that of ActRIIB, and the patterns of expression were similar, although not identical. The most intense sites of Activin Receptor gene expression were the hippocampal formation, especially the dentate gyrus (ActRII), taenia tecta, and induseum griseum; the amygdala, particularly the amygdaloid-hippocampal transition zone; and throughout the cortical mantle, including the primary olfactory cortex (piriform cortex and olfactory tubercle); other regions of the cortex showing lesser degrees of hybridization included the cingulate cortex, claustrum, entorhinal cortex, and subiculum. In addition, moderate levels of expression were observed in several hypothalamic areas involved in n...
Martin M. Matzuk - One of the best experts on this subject based on the ideXlab platform.
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uterine Activin Receptor like kinase 5 is crucial for blastocyst implantation and placental development
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Jia Peng, Diana Monsivais, Hua Zhong, Stephanie A Pangas, Martin M. MatzukAbstract:Members of the transforming growth factor β (TGF-β) superfamily are key regulators in most developmental and physiological processes. However, the in vivo roles of TGF-β signaling in female reproduction remain uncertain. Activin Receptor-like kinase 5 (ALK5) is the major type 1 Receptor for the TGF-β subfamily. Absence of ALK5 leads to early embryonic lethality because of severe defects in vascular development. In this study, we conditionally ablated uterine ALK5 using progesterone Receptor-cre mice to define the physiological roles of ALK5 in female reproduction. Despite normal ovarian functions and artificial decidualization in conditional knockout (cKO) mice, absence of uterine ALK5 resulted in substantially reduced female reproduction due to abnormalities observed at different stages of pregnancy, including implantation defects, disorganization of trophoblast cells, fewer uterine natural killer (uNK) cells, and impairment of spiral artery remodeling. In our microarray analysis, genes encoding proteins involved in cytokine–cytokine Receptor interactions and NK cell-mediated cytotoxicity were down-regulated in cKO decidua compared with control decidua. Flow cytometry confirmed a 10-fold decrease in uNK cells in cKO versus control decidua. According to these data, we hypothesize that TGF-β acts on decidual cells via ALK5 to induce expression of other growth factors and cytokines, which are key regulators in luminal epithelium proliferation, trophoblast development, and uNK maturation during pregnancy. Our findings not only generate a mouse model to study TGF-β signaling in female reproduction but also shed light on the pathogenesis of many pregnancy complications in human, such as recurrent spontaneous abortion, preeclampsia, and intrauterine growth restriction.
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prevention of cachexia like syndrome development and reduction of tumor progression in inhibin deficient mice following administration of a chimeric Activin Receptor type ii murine fc protein
Molecular Human Reproduction, 2007Co-Authors: Qinglei Li, Jasbir Seehra, Ravi Kumar, Kathryn W Underwood, Anne E Oconnor, Kate L Loveland, Martin M. MatzukAbstract:Inhibin is a secreted tumor suppressor, and inhibin a null mice develop gonadal sex cord-stromal tumors with 100% penetrance at an early age. Inhibin-deficient mice die of a severe wasting syndrome due to increased Activin signaling through Activin Receptor type II. The current study was designed to assess the in vivo effects of an Activin antagonist, a chimeric Activin Receptor type II fused to the Fc region of a murine IgG2a (ActRII-mFc), administered transiently to the inhibin-deficient mice. Results showed that the severe weight loss was prevented in the ActRII-mFc-treated mice, FSH levels were reduced, and an extended life span was observed for these mice compared with phosphate-buffered saline-treated controls. Although ActRII-mFc treatment did not seem to prevent the formation of gonadal tumors, tumors were smaller in the majority of experimentally treated mice and were characterized by the presence of variable numbers and sizes of cysts in contrast to the solid hemorrhagic tumors that typically developed in the controls. Moreover, the ActRII-mFc-treated mice were less anemic, and their livers and stomachs were histologically normal. In summary, this study demonstrated that in vivo administration of the Activin antagonist, ActRII-mFc, not only prevents the cachexia-like symptoms in the inhibin-deficient mouse model, but also reduces tumor progression. These results support an essential role of Activins in the cachexia-like syndrome development and implicate Activins as growth-promoting factors in gonadal tumor progression. The current findings have potential implications in the design of new drugs or strategies for the treatment of ovarian and testicular tumors and other conditions where ligands signal through ActRII.
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Impaired Male Sexual Behavior in Activin Receptor Type II Knockout Mice
Biology of Reproduction, 2005Co-Authors: Xiaoping Ma, Andrea Reyna, Shailaja K. Mani, Martin M. Matzuk, T. Rajendra KumarAbstract:Integration of multiple hormonal and neuronal signaling pathways in the medial preoptic area (mPOA) is required for elicitation of male sexual behavior in most vertebrates. Perturbation of nitric oxide synthase (NOS) activity in the mPOA causes significant defects in male sexual behavior. Although Activins and their signaling components are highly expressed throughout the brain, including the mPOA, their functional significance in the central nervous system (CNS) is unknown. Here, we demonstrate a neurophysiologic role for Activin signaling in male reproductive behavior. Adult Activin Receptor type II null (Acvr2 � /� ) male mice display multiple reproductive behavioral deficits, including delayed initiation of copulation, reduced mount, and intromission frequencies, and increased mount, intromission, and ejaculation latencies. These behavioral defects in the adult mice are independent of gonadotropin-releasing hormone (GnRH) homeostasis or mating-induced changes in luteinizing hormone (LH) and testosterone levels. The impairment in behavior can be correlated to the nitric oxide content in the CNS because Acvr2 � /� males have decreased NOS activity in the mPOA but not the rest of the hypothalamus or cortex. Olfactory acuity tests confirmed that Acvr2 � /� mice have no defects in general odor or pheromone recognition. In addition, motor functions are not impaired and the mutants demonstrate normal neuromuscular coordination and balance. Furthermore, the penile histology in mutant mice appears normal, with no significant differences in the expression of penile differentiation marker genes compared with controls, suggesting the observed behavioral phenotypes are not due to structural defects in the penis. Our studies identify a previously unrecognized role of Activin signaling in male sexual behavior and suggest that Activins and/or related family members are upstream regulators of NOS activity within the mPOA of the forebrain.
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Male Reproductive Phenotypes in Double Mutant Mice Lacking Both FSHβ and Activin Receptor IIA
Endocrinology, 2001Co-Authors: T. Rajendra Kumar, Simona Varani, Nigel G. Wreford, Nancy M. Telfer, D. M. De Kretser, Martin M. MatzukAbstract: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, FSHβ 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 si...
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Activin signaling through Activin Receptor type ii causes the cachexia like symptoms in inhibin deficient mice
Molecular Endocrinology, 1996Co-Authors: Katherine A Coerver, Allan Bradley, Teresa K Woodruff, Milton J Finegold, Jennie P Mather, Martin M. MatzukAbstract:Activins and inhibins, members of the transforming growth factor-p superfamily, are involved in diverse physiological and developmental processes. We have previously shown that mice deficient in cY-inhibin develop gonadal sex cord-stromal tumors at an early age. The tumor development is rapidly followed by a wasting syndrome that includes severe weight loss, hepatocellular necrosis around the central vein, and depletion of the parieta1 cells in the glandular stomach. The liver histology in inhibin-deficient mice is similar to the pathological effects of short-term treatment of rats and mice with recombinant Activin A. Consistent with these findings, we have shown that the gonadal tumors in the inhibit+deficient mice secrete high levels of Activins. In addition, Northern blot analysis has localized Activin Receptor type II (ActRII) to the liver. Based on these studies, we postulated that tumor-produced Activins act through ActRll to cause the wasting syndrome in inhibin-deficient mice. To test this hypothesis and determine the significance of elevated levels of Activin signaling through ActRll in viva, we generated compound homozygous mutant mice deficient in both cu-inhibin and ActRII. Despite the continued development of gonadal sex cord-stromal tumors and elevated serum levels of Activin A and B, the compound homozygous mutant mice suffered no unusual weight loss, and the stomachs and livers of the majority of the mice were histologically normal. These results demonstrate that increased levels of Activin signaling through ActRll
Paul S Oh - One of the best experts on this subject based on the ideXlab platform.
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arterial endothelium specific Activin Receptor like kinase 1 expression suggests its role in arterialization and vascular remodeling
Circulation Research, 2003Co-Authors: Tsugio Seki, Paul S OhAbstract:Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVM). Two genes are linked to HHT: endoglin ( ENG ) in HHT1 and Activin Receptor-like kinase 1 ( ACVRL1 ; ALK1 ) in HHT2. Although both genes are involved in the transforming growth factor β signaling pathways, the pathogenetic mechanisms for HHT remain elusive. It was shown that mutations in the Alk1 gene in mice and zebrafish resulted in an embryonic lethal phenotype due to severe dilation of blood vessels. We created a novel null mutant mouse line for Alk1 ( Alk1 lacZ ) by replacing its exons, including the one that encodes the transmembrane domain, with the β-galactosidase gene. Using Alk1 lacZ mice, we show that Alk1 is predominantly expressed in developing arterial endothelium. Alk1 expression is greatly diminished in adult arteries, but is induced in preexisting feeding arteries and newly forming arterial vessels during wound healing and tumor angiogenesis. We also show that hemodynamic changes, which require vascular remodeling, may regulate Alk1 expression. Our studies suggest the role of Alk1 signaling in arterialization and remodeling of arteries. Contrary to the current view of HHT as venous disease, our findings suggest that the arterioles rather than the venules are the primary vessels affected by the loss of an Alk1 allele, and that blood vessels with reduction in Alk1 expression may harbor defects in responding to demands for vascular remodeling.
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Activin Receptor patterning of foregut organogenesis
Genes & Development, 2000Co-Authors: Matthias Hebrok, Heinrich Schrewe, En Li, Paul S Oh, Erin B Harmon, Douglas A. MeltonAbstract:Organs, including the lungs, stomach, spleen and pancreas, develop at stereotyped positions along the anterior-posterior (AP) axis of the vertebrate foregut. Signaling pathways that govern skeletal and central nervous system AP patterning have been identified (Sasai and De Robertis 1997; McPherron et al. 1999), but comparatively little is known about the genetic programs that specify foregut organ position, morphogenesis, and cellular differentiation. Restricted endodermal expression of Sonic hedgehog (Shh), a member of the Hedgehog family of secreted signaling proteins, specifies domains within the gut to generate boundaries and proper differentiation of the stomach, spleen, pancreas, intestines, and respiratory tract (Roberts et al. 1995; Apelqvist et al. 1997; Kim et al. 1997a,b; Hebrok et al. 1998; Kim and Melton 1998). Shh misexpression or inactivation in mice leads to defects in foregut organogenesis that mimic common human congenital disorders, including tracheal-esophageal fistula, heterotopic pancreas, annular pancreas, and hyposplenism (Apelqvist et al. 1997; Hebrok et al. 1998, 2000; Kim and Melton 1998; Litingtung et al. 1998; Pepicelli et al. 1998). Activins, members of the transforming growth factor-β (TGF-β) superfamily, govern embryonic axial patterning (Hoodless et al. 1999), and may restrict Shh expression in embryonic chicks (Levin et al. 1995; Hebrok et al. 1998). Type II Activin Receptors, ActRIIA and ActRIIB, are cell-surface protein kinases, and previous work has demonstrated that ActRIIB-mediated signaling controls both AP pattern of the axial skeleton and lateral asymmetry of heart and lungs (Oh and Li 1997). Following gastrulation, and during organogenesis in mid-gestational embryos, both ActRIIA and ActRIIB are expressed in the primordia of foregut organs, including lungs, stomach, intestines, and pancreas (Feijen et al. 1994; Manova et al. 1995; Verschueren et al. 1995). In adult mice, both ActRIIA and ActRIIB are expressed in pancreatic islet cells (Yamaoka et al. 1998; Shiozaki et al. 1999). Thus, ActRIIA and ActRIIB are transcribed in foregut organ anlagen before and during morphogenesis and cellular differentiation. To study type II Activin Receptor function in foregut patterning, we examined embryos with combinations of ActRIIA and ActRIIB null mutations derived by gene targeting (Oh and Li 1997; Song et al. 1999). In this study we show that type II Activin Receptors are crucial for normal development of many foregut organs, and that these Receptors have a particularly critical role in development and function of the endocrine pancreas.
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Activin Receptor like kinase 1 modulates transforming growth factor β1 signaling in the regulation of angiogenesis
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Paul S Oh, K. A. Goss, Patricia K Donahoe, Y. Yi, Kohei Miyazono, T. Imamura, Tsugio Seki, Peter Ten Dijke, Li Li, En LiAbstract:The Activin Receptor-like kinase 1 (ALK1) is a type I Receptor for transforming growth factor-β (TGF-β) family proteins. Expression of ALK1 in blood vessels and mutations of the ALK1 gene in human type II hereditary hemorrhagic telangiectasia patients suggest that ALK1 may have an important role during vascular development. To define the function of ALK1 during development, we inactivated the ALK1 gene in mice by gene targeting. The ALK1 homozygous embryos die at midgestation, exhibiting severe vascular abnormalities characterized by excessive fusion of capillary plexes into cavernous vessels and hyperdilation of large vessels. These vascular defects are associated with enhanced expression of angiogenic factors and proteases and are characterized by deficient differentiation and recruitment of vascular smooth muscle cells. The blood vessel defects in ALK1-deficient mice are reminiscent of mice lacking TGF-β1, TGF-β type II Receptor (TβR-II), or endoglin, suggesting that ALK1 may mediate TGF-β1 signal in endothelial cells. Consistent with this hypothesis, we demonstrate that ALK1 in endothelial cells binds to TGF-β1 and TβR-II. Furthermore, the ALK1 signaling pathway can inhibit TGF-β1-dependent transcriptional activation mediated by the known TGF-β1 type I Receptor, ALK5. 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.
Tsugio Seki - One of the best experts on this subject based on the ideXlab platform.
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arterial endothelium specific Activin Receptor like kinase 1 expression suggests its role in arterialization and vascular remodeling
Circulation Research, 2003Co-Authors: Tsugio Seki, Paul S OhAbstract:Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVM). Two genes are linked to HHT: endoglin ( ENG ) in HHT1 and Activin Receptor-like kinase 1 ( ACVRL1 ; ALK1 ) in HHT2. Although both genes are involved in the transforming growth factor β signaling pathways, the pathogenetic mechanisms for HHT remain elusive. It was shown that mutations in the Alk1 gene in mice and zebrafish resulted in an embryonic lethal phenotype due to severe dilation of blood vessels. We created a novel null mutant mouse line for Alk1 ( Alk1 lacZ ) by replacing its exons, including the one that encodes the transmembrane domain, with the β-galactosidase gene. Using Alk1 lacZ mice, we show that Alk1 is predominantly expressed in developing arterial endothelium. Alk1 expression is greatly diminished in adult arteries, but is induced in preexisting feeding arteries and newly forming arterial vessels during wound healing and tumor angiogenesis. We also show that hemodynamic changes, which require vascular remodeling, may regulate Alk1 expression. Our studies suggest the role of Alk1 signaling in arterialization and remodeling of arteries. Contrary to the current view of HHT as venous disease, our findings suggest that the arterioles rather than the venules are the primary vessels affected by the loss of an Alk1 allele, and that blood vessels with reduction in Alk1 expression may harbor defects in responding to demands for vascular remodeling.
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Arterial endothelium-specific Activin Receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling
Circulation Research, 2003Co-Authors: Tsugio Seki, Jihye Yun, S. Paul OhAbstract:Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVM). Two genes are linked to HHT: endoglin (ENG) in HHT1 and Activin Receptor-like kinase 1 (ACVRL1; ALK1) in HHT2. Although both genes are involved in the transforming growth factor beta signaling pathways, the pathogenetic mechanisms for HHT remain elusive. It was shown that mutations in the Alk1 gene in mice and zebrafish resulted in an embryonic lethal phenotype due to severe dilation of blood vessels. We created a novel null mutant mouse line for Alk1 (Alk1lacZ) by replacing its exons, including the one that encodes the transmembrane domain, with the beta-galactosidase gene. Using Alk1lacZ mice, we show that Alk1 is predominantly expressed in developing arterial endothelium. Alk1 expression is greatly diminished in adult arteries, but is induced in preexisting feeding arteries and newly forming arterial vessels during wound healing and tumor angiogenesis. We also show that hemodynamic changes, which require vascular remodeling, may regulate Alk1 expression. Our studies suggest the role of Alk1 signaling in arterialization and remodeling of arteries. Contrary to the current view of HHT as venous disease, our findings suggest that the arterioles rather than the venules are the primary vessels affected by the loss of an Alk1 allele, and that blood vessels with reduction in Alk1 expression may harbor defects in responding to demands for vascular remodeling.
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Activin Receptor like kinase 1 modulates transforming growth factor β1 signaling in the regulation of angiogenesis
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Paul S Oh, K. A. Goss, Patricia K Donahoe, Y. Yi, Kohei Miyazono, T. Imamura, Tsugio Seki, Peter Ten Dijke, Li Li, En LiAbstract:The Activin Receptor-like kinase 1 (ALK1) is a type I Receptor for transforming growth factor-β (TGF-β) family proteins. Expression of ALK1 in blood vessels and mutations of the ALK1 gene in human type II hereditary hemorrhagic telangiectasia patients suggest that ALK1 may have an important role during vascular development. To define the function of ALK1 during development, we inactivated the ALK1 gene in mice by gene targeting. The ALK1 homozygous embryos die at midgestation, exhibiting severe vascular abnormalities characterized by excessive fusion of capillary plexes into cavernous vessels and hyperdilation of large vessels. These vascular defects are associated with enhanced expression of angiogenic factors and proteases and are characterized by deficient differentiation and recruitment of vascular smooth muscle cells. The blood vessel defects in ALK1-deficient mice are reminiscent of mice lacking TGF-β1, TGF-β type II Receptor (TβR-II), or endoglin, suggesting that ALK1 may mediate TGF-β1 signal in endothelial cells. Consistent with this hypothesis, we demonstrate that ALK1 in endothelial cells binds to TGF-β1 and TβR-II. Furthermore, the ALK1 signaling pathway can inhibit TGF-β1-dependent transcriptional activation mediated by the known TGF-β1 type I Receptor, ALK5. 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.
Kohei Miyazono - One of the best experts on this subject based on the ideXlab platform.
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Activin Receptor like kinase 1 modulates transforming growth factor β1 signaling in the regulation of angiogenesis
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Paul S Oh, K. A. Goss, Patricia K Donahoe, Y. Yi, Kohei Miyazono, T. Imamura, Tsugio Seki, Peter Ten Dijke, Li Li, En LiAbstract:The Activin Receptor-like kinase 1 (ALK1) is a type I Receptor for transforming growth factor-β (TGF-β) family proteins. Expression of ALK1 in blood vessels and mutations of the ALK1 gene in human type II hereditary hemorrhagic telangiectasia patients suggest that ALK1 may have an important role during vascular development. To define the function of ALK1 during development, we inactivated the ALK1 gene in mice by gene targeting. The ALK1 homozygous embryos die at midgestation, exhibiting severe vascular abnormalities characterized by excessive fusion of capillary plexes into cavernous vessels and hyperdilation of large vessels. These vascular defects are associated with enhanced expression of angiogenic factors and proteases and are characterized by deficient differentiation and recruitment of vascular smooth muscle cells. The blood vessel defects in ALK1-deficient mice are reminiscent of mice lacking TGF-β1, TGF-β type II Receptor (TβR-II), or endoglin, suggesting that ALK1 may mediate TGF-β1 signal in endothelial cells. Consistent with this hypothesis, we demonstrate that ALK1 in endothelial cells binds to TGF-β1 and TβR-II. Furthermore, the ALK1 signaling pathway can inhibit TGF-β1-dependent transcriptional activation mediated by the known TGF-β1 type I Receptor, ALK5. 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.
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Activin Receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis
Proceedings of the National Academy of Sciences, 2000Co-Authors: S P Oh, Peter Ten Dijke, K. A. Goss, Patricia K Donahoe, Y. Yi, Kohei Miyazono, T. Imamura, T. Seki, Lei Li, S. KimAbstract:The Activin Receptor-like kinase 1 (ALK1) is a type I Receptor for transforming growth factor-beta (TGF-beta) family proteins. Expression of ALK1 in blood vessels and mutations of the ALK1 gene in human type II hereditary hemorrhagic telangiectasia patients suggest that ALK1 may have an important role during vascular development. To define the function of ALK1 during development, we inactivated the ALK1 gene in mice by gene targeting. The ALK1 homozygous embryos die at midgestation, exhibiting severe vascular abnormalities characterized by excessive fusion of capillary plexes into cavernous vessels and hyperdilation of large vessels. These vascular defects are associated with enhanced expression of angiogenic factors and proteases and are characterized by deficient differentiation and recruitment of vascular smooth muscle cells. The blood vessel defects in ALK1-deficient mice are reminiscent of mice lacking TGF-beta1, TGF-beta type II Receptor (TbetaR-II), or endoglin, suggesting that ALK1 may mediate TGF-beta1 signal in endothelial cells. Consistent with this hypothesis, we demonstrate that ALK1 in endothelial cells binds to TGF-beta1 and TbetaR-II. Furthermore, the ALK1 signaling pathway can inhibit TGF-beta1-dependent transcriptional activation mediated by the known TGF-beta1 type I Receptor, ALK5. 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.
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Activin Receptor like kinases a novel subclass of cell surface Receptors with predicted serine threonine kinase activity
Oncogene, 1993Co-Authors: Ten Dijke P, Hidenori Ichijo, Petra Franzen, P Schulz, Jan Saras, H Toyoshima, C H Heldin, Kohei MiyazonoAbstract:Abstract Human cDNA clones encoding four novel putative transmembrane protein serine/threonine kinases, denoted Activin Receptor-like kinase (ALK) -1, -2, -3 and -4, were obtained using a polymerase chain reaction (PCR)-based strategy. The PCR primers were designed based upon the sequence similarity between the Activin Receptor type II and Daf-1. The cDNA clones for ALK-1, -2 and -3 encode complete proteins of 503, 509 and 532 amino acids respectively. The ALK-4 cDNA is incomplete and the predicted protein of 383 amino acids has a truncated extracellular domain. The ALKs share similar domain structures, comprising predicted signal sequences at the N-terminals, followed by hydrophilic cysteine-rich ligand-binding domains, single hydrophobic transmembrane regions and C-terminal intracellular portions that consist almost entirely of putative serine/threonine kinase domains. 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. However, the sequence identities are higher (60-79%) between ALK-1, -2, -3 and -4, suggesting that they form a subfamily among the putative Receptor serine/threonine kinases. The extracellular domains of ALKs show only little sequence identity to other putative Receptor serine/threonine kinases, but the cysteine residues are conserved. Their structural properties suggest that ALK-1 to -4 are Receptors that may bind ligands that are members of the TGF-beta superfamily. The expression of mRNA in human tissues varied for the different ALKs; ALK-2 and ALK-4 showed ubiquitous tissue expression patterns, whereas the distribution of ALK-1 and ALK-3 varied strongly between different tissues with more restricted expression patterns. These results suggest that each ALK may have different in vivo functions.
