title: Nodal induces apoptosis through activation of the ALK7 signaling pathway in pancreatic INS-1 β-cells.
abstract: We demonstrated previously that the activation of ALK7 (activin receptor-like kinase-7), a member of the type I receptor serine/threonine kinases of the TGF-β superfamily, resulted in increased apoptosis and reduced proliferation through suppression of Akt signaling and the activation of Smad2-dependent signaling pathway in pancreatic β-cells. Here, we show that Nodal activates ALK7 signaling and regulates β-cell apoptosis. We detected Nodal expression in the clonal β-cell lines and rodent islet β-cells. Induction of β-cell apoptosis by treatment with high glucose, palmitate, or cytokines significantly increased Nodal expression in clonal INS-1 β-cells and isolated rat islets. The stimuli induced upregulation of Nodal expression levels were associated with elevation of ALK7 protein and enhanced phosphorylated Smad3 protein. Nodal treatment or overexpression of Nodal dose- or time-dependently increased active caspase-3 levels in INS-1 cells. Nodal-induced apoptosis was associated with decreased Akt phosphorylation and reduced expression level of X-linked inhibitor of apoptosis (XIAP). Remarkably, overexpression of XIAP or constitutively active Akt, or ablation of Smad2/3 activity partially blocked Nodal-induced apoptosis. Furthermore, siRNA-mediated ALK7 knockdown significantly attenuated Nodal-induced apoptosis of INS-1 cells. We suggest that Nodal-induced apoptosis in β-cells is mediated through ALK7 signaling involving the activation of Smad2/3-caspase-3 and the suppression of Akt and XIAP pathways and that Nodal may exert its biological effects on the modulation of β-cell survival and β-cell mass in an autocrine fashion.
authors.affiliation: Division of Endocrinology and Metabolism, the Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.forename: Fengjie
authors.initials: F
authors.lastname: Huang
authors.forename: Mengxiong
authors.initials: M
authors.lastname: Tang
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.forename: Nina
authors.initials: N
authors.lastname: Zhang
authors.forename: Akis
authors.initials: A
authors.lastname: Amfilochiadis
authors.forename: Yiming
authors.initials: Y
authors.lastname: Li
authors.forename: Renming
authors.initials: R
authors.lastname: Hu
authors.forename: Tianru
authors.initials: T
authors.lastname: Jin
authors.forename: Chun
authors.initials: C
authors.lastname: Peng
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D055457:Nodal Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D046509:Tissue Culture Techniques; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D055457:Nodal Protein; D012333:RNA, Messenger; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D030201:Activin Receptors, Type I; C486044:Acvr1c protein, rat