The MH1 Domains of Smad2 and Smad3 Are Involved in the Regulation of the ALK7 Signals

Watanabe, Rie; Yamada, Yoshio; Ihara, Yu; Someya, Yoshimichi; Kubota, Akira; Kagimoto, Shinji; Kuroe, Akira; Iwakura, Toshio; Shen, Zhenping; Inada, Akira; Adachi, Tomohiko; Ban, Nobuhiro; Miyawaki, Kazumasa; Sunaga, Yasuhiro; Tsuda, Kinsuke; Seino, Yutaka

doi:10.1006/bbrc.1998.0118

Cited by 34 publications

(25 citation statements)

References 15 publications

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“…We detected ALK7 transcripts and proteins in the rat pancreatic islet cells and INS-1 cells. The findings are in good agreement with previous studies by Watanabe et al [7], who detected ALK7 mRNA in MIN6 cells, and by Tsuchida and colleagues [28], who demonstrated that ALK7 proteins were localised to insulin-positive cells in murine pancreatic tissue. We also detected ALK7 expression in the alpha cells, although the cellular distribution and the molecular weight differed from ALK7 found in the beta cells.…”

Section: Discussionsupporting

confidence: 93%

“…ALK7-induced apoptosis is mediated by Smad2-caspase-3 pathways and prevented by Akt ALK7 activation is known to initiate the R-Smad cascade in the induction of apoptosis, involving phosphorylation of Smad2/3 proteins [7]. To explore whether Smad2 is involved in ALK7 action in INS-1 cells, we examined whether ALK7 could induce Smad2 phosphorylation and whether DN-Smad2 could block the pro-apoptotic action of ALK7.…”

Section: Activation Of Alk7 Suppresses Akt Activationmentioning

confidence: 99%

“…Type II receptors, upon ligand binding, recruit and phosphorylate type I receptors at an intracellular segment consisting of glycine and serine residues (GS box) [1]. The two receptors form a functional heteromeric receptor complex and initiate intracellular signalling cascades by phosphorylating the Smad proteins [6,7]. The phosphorylated Smad protein complexes are then translocated into the nucleus to modulate target gene transcription (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Activin receptor-like kinase 7 induces apoptosis of pancreatic beta cells and beta cell lines

Zhang

Kumar

et al. 2006

Diabetologia

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Aims/hypothesis: Activin receptor-like kinase 7 (ALK7), a member of the type I receptor serine/threonine kinases of the TGF-β superfamily, was recently reported to regulate cell proliferation and apoptosis. We hypothesised that ALK7 may play a role in modulating pancreatic beta cell proliferation and/or apoptosis. Methods: We detected ALK7 expression in beta cells using RT-PCR, immunostaining and western blotting. Constitutively active, dominant negative or wild-type ALK7 was introduced into beta cells using adenoviral delivery. Proliferation was assessed using 3 H-thymidine incorporation and apoptosis was quantified using terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling detection, DNA degradation analysis and caspase-3 assays. Results: Induction of constitutively active ALK7 in beta cells resulted in growth inhibition and enhanced apoptosis; no effect was seen with INS-1 cells expressing wild-type or dominant negative ALK7. Elevated glucose concentrations and fatty acid (palmitate) markedly increased expression levels of ALK7 transcripts and proteins in INS-1 and rat islets and increased beta cell apoptosis. Activation of ALK7 increased Smad2 phosphorylation, reduced protein kinase B (Akt) kinase activity and was associated with increased levels of the bioactive forms of caspase-3, whereas co-expression of constitutively active ALK7 with dominant negative Smad2 or constitutively active Akt significantly diminished ALK7-induced growth inhibition and apoptosis in INS-1 cells. Although overexpression of constitutively active Akt significantly reduced ALK7-induced growth inhibition and ALK7-enhanced beta cell apoptosis, ALK7-stimulated Smad2 phosphorylation was not affected. Conclusions/ interpretation: These results suggest that the pancreatic beta cell apoptosis induced by ALK7 activation occurs via the activation of two distinct downstream pathways: the suppression of Akt activation and the activation of the Smad2-caspase-3 cascade.

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Section: Discussionsupporting

confidence: 93%

Section: Activation Of Alk7 Suppresses Akt Activationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activin receptor-like kinase 7 induces apoptosis of pancreatic beta cells and beta cell lines

Zhang

Kumar

et al. 2006

Diabetologia

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“…The function of ALK7 as a type I receptor was confirmed with a constitutively active mutant form that activated a TGF-␤/activin response reporter (6). ALK7 has also been found to activate some components of the Smad pathway, such as Smad2 and Smad3, in fetal and adult rat pancreas (8). In the rat pheochromocytoma PC12 cell line, ALK7 not only activated both Smad2, Smad3, and the mitogenactivated protein kinases (MAPK) of extracellular signal-regulated kinase and c-Jun NH 2 -terminal kinase (JNK), but it inhibited cell proliferation as well (9).…”

mentioning

confidence: 85%

Activin Receptor-like Kinase-7 Induces Apoptosis through Activation of MAPKs in a Smad3-dependent Mechanism in Hepatoma Cells

Kim

Gelder

Kim

et al. 2004

Journal of Biological Chemistry

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Activin receptor-like kinase (ALK)7 is a type I serine/ threonine kinase receptor of the transforming growth factor (TGF)-␤ family of proteins that has similar properties to other type I receptors when activated. To see whether ALK7 can induce apoptosis as can some of the other ALK proteins, we infected the FaO rat hepatoma cell line with adenovirus expressing a constitutively active form of the ALK7. Cells infected with active ALK7 adenovirus showed an apoptotic-positive phenotype, as opposed to those that were infected with a control protein. DNA fragmentation assays and fluorescence-activated cell sorter analysis also indicated that ALK7 infection induced apoptosis in FaO cells. We also confirmed this finding in Hep3B human hepatoma cells by transiently transfecting the constitutively active form of ALK7, ALK7(T194D). Investigation into the downstream targets and mechanisms involved in ALK7-induced apoptosis revealed that the TGF-␤ signaling intermediates, Smad2 and -3, were activated, as well as the MAPKs JNK and p38. In addition, caspase-3 and -9 were also activated, and cytochrome c release from the mitochondria was observed. Short interfering RNA-mediated inhibition of Smad3 markedly suppressed ALK7-induced caspase-3 activation. Treatment with protein synthesis inhibitors or the expression of the dominantnegative form of the stress-activated protein/extracellular signal-regulated kinase 1 abolished not only JNK activation but apoptosis as well. Taken together, these results suggest that ALK7 induces apoptosis through activation of the traditional TGF-␤ pathway components, thus resulting in new gene transcription and JNK and p38 activation that initiates cross-talk with the cellular stress death pathway and ultimately leads to apoptosis.

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“…ALK7 is dispensable for mouse embryogenesis (17), which suggests alternative functions for this receptor in postnatal development and tissue homeostasis. ALK7 is expressed in several organs involved in metabolic regulation, including pancreas, adipose tissue, gut, and brain (16,(18)(19)(20), but the physiological function of this receptor has been unknown. In this study, we have investigated the roles of ALK7 in metabolic control and the organization and function of the endocrine pancreas.…”

mentioning

confidence: 99%

Activin B receptor ALK7 is a negative regulator of pancreatic β-cell function

Bertolino

Holmberg

Reissmann

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

113

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All major cell types in pancreatic islets express the transforming growth factor (TGF)-␤ superfamily receptor ALK7, but the physiological function of this receptor has been unknown. Mutant mice lacking ALK7 showed normal pancreas organogenesis but developed an age-dependent syndrome involving progressive hyperinsulinemia, reduced insulin sensitivity, liver steatosis, impaired glucose tolerance, and islet enlargement. Hyperinsulinemia preceded the development of any other defect, indicating that this may be one primary consequence of the lack of ALK7. In agreement with this, mutant islets showed enhanced insulin secretion under sustained glucose stimulation, indicating that ALK7 negatively regulates glucose-stimulated insulin release in ␤-cells. Glucose increased expression of ALK7 and its ligand activin B in islets, but decreased that of activin A, which does not signal through ALK7. The two activins had opposite effects on Ca 2؉ signaling in islet cells, with activin A increasing, but activin B decreasing, glucosestimulated Ca 2؉ influx. On its own, activin B had no effect on WT cells, but stimulated Ca 2؉ influx in cells lacking ALK7. In accordance with this, mutant mice lacking activin B showed hyperinsulinemia comparable with that of Alk7 ؊/؊ mice, but double mutants showed no additive effects, suggesting that ALK7 and activin B function in a common pathway to regulate insulin secretion. These findings uncover an unexpected antagonism between activins A and B in the control of Ca 2؉ signaling in ␤-cells. We propose that ALK7 plays an important role in regulating the functional plasticity of pancreatic islets, negatively affecting ␤-cell function by mediating the effects of activin B on Ca 2؉ signaling.T he signaling networks controlling metabolic processes are highly regulated and integrate the actions of both positively and negatively acting components from many different signaling pathways. Members of the transforming growth factor (TGF)-␤ superfamily, including TGF-␤s, growth and differentiation factors (GDFs), bone morphogenetic proteins (BMPs) and activins, have been implicated in the regulation of several metabolic processes. These ligands signal via distinct complexes of type I and type II receptor serine-threonine kinases, each binding to different classes of TGF-␤ ligands (1, 2). The main and most widely studied signaling pathway downstream of these receptors involves activation and nuclear translocation of Smad proteins, which in turn regulate gene transcription through multiple interactions with distinct sets of transcription factors in a cell type-specific manner (1, 2). Although less well understood, Smad-independent pathways have also been described in a variety of cell systems and involve the activation of MAP kinases, small GTPases, and Ca 2ϩ mobilization (3).Identification of cell-intrinsic factors controlling the specification and function of pancreatic endocrine cells is of major importance for understanding the regulation of blood-glucose homeostasis. The characterization of signals regul...

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The MH1 Domains of Smad2 and Smad3 Are Involved in the Regulation of the ALK7 Signals

Cited by 34 publications

References 15 publications

Activin receptor-like kinase 7 induces apoptosis of pancreatic beta cells and beta cell lines

Activin receptor-like kinase 7 induces apoptosis of pancreatic beta cells and beta cell lines

Activin Receptor-like Kinase-7 Induces Apoptosis through Activation of MAPKs in a Smad3-dependent Mechanism in Hepatoma Cells

Activin B receptor ALK7 is a negative regulator of pancreatic β-cell function

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