title: Aspp2 negatively regulates body growth but not developmental timing by modulating IRS signaling in zebrafish embryos.
abstract: The growth and developmental rate of developing embryos and fetus are tightly controlled and coordinated to maintain proper body shape and size. The insulin receptor substrate (IRS) proteins, key intracellular transducers of insulin and insulin-like growth factor signaling, play essential roles in the regulation of growth and development. A short isoform of apoptosis-stimulating protein of p53 2 (ASPP2) was recently identified as a binding partner of IRS-1 and IRS-2 in mammalian cells in vitro. However, it is unclear whether ASPP2 plays any role in vertebrate embryonic growth and development. Here, we show that zebrafish Aspp2a and Aspp2b negatively regulate embryonic growth without affecting developmental rate. Human ASPP2 had similar effects on body growth in zebrafish embryos. Aspp2a and 2b inhibit Akt signaling. This inhibition was reversed by coinjection of myr-Akt1, a constitutively active form of Akt1. Zebrafish Aspp2a and Aspp2b physically bound with Irs-1, and the growth inhibitory effects of ASPP2/Aspp2 depend on the presence of their ankyrin repeats and SH3 domains. These findings uncover a novel role of Aspp2 in regulating vertebrate embryonic growth.
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
authors.forename: Chengdong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Luan
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
authors.forename: Yunzhang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hakuno
authors.affiliation: Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology (C.D.), University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Cunming
authors.initials: C
authors.lastname: Duan
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China. Electronic address: jfzhou@ouc.edu.cn.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D049628:Body Size / Q000502:physiology; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013002:Somatomedins / Q000378:metabolism; D019170:Somites / Q000196:embryology / Q000502:physiology; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins; D018909:src Homology Domains / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017487:Ankyrins; D051017:Apoptosis Regulatory Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D013002:Somatomedins; C090468:TP53BP2 protein, human; D029961:Zebrafish Proteins; C000592876:tp53bp2a protein, zebrafish; D051057:Proto-Oncogene Proteins c-akt
keywords: 5-bromo-2′-deoxyuridine; AO; Acridine orange; Akt; Akt/PKB; Ank; Apoptosis-stimulating protein of p53 2; BrdU; EGFP; Embryonic growth; Erk; HEK; IGF-I receptor; IGF-IR; IGFs; IRS; Insulin receptor substrate; SH3; Src homology 3; Zebrafish; aa; amino acids; ankyrin repeats; enhanced GFP; extracellular signal-regulated kinases; hour post fertilization; hpf; human embryonic kidney; insulin receptor substrate; insulin-like growth factors; protein kinase B