Structural and Functional Analysis of the Amphioxus IGFBP Gene Uncovers Ancient Origin of IGF-Independent Functions

doi:10.1210/en.2013-1201

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	Structural and Functional Analysis of the Amphioxus IGFBP Gene Uncovers Ancient Origin of IGF-Independent Functions
	Zhou, Jianfeng 1,2; Xiang, Jianhai5 ; Zhang, Shicui 4; Duan, Cunming 1; Duan, CM
	2013-10-01
发表期刊	ENDOCRINOLOGY
ISSN	0013-7227
卷号	154 期号:10 页码:3753-3763
文章类型	Article
摘要	IGFs play key roles in regulating vertebrate development, growth, reproduction, and aging. In extracellular fluids, IGFs are bound and regulated by a family of IGF-binding proteins (IGFBPs). Although all known IGFBPs are secreted proteins, some are also found in the nucleus and possess IGF-independent activities. When and how these distinct modes of biological actions have evolved is unknown. In this study, we identified and analyzed an IGFBP gene from amphioxus. Amphioxus shares a common ancestor with the modern vertebrate lineage that dates back to more than 520 million years ago. The amphioxus IGFBP shares all major structural characteristics of vertebrate IGFBPs. Phylogenetic analyses place it in a basal position in the IGFBP lineage. Ligand blot analysis reveals that amphioxus IGFBP does not bind to IGF-I or -II. Changing its Phe70 into Leu, however, is sufficient to convert it into a functional IGF binder. When tested in cultured cells, amphioxus IGFBP is localized in the nucleus, and this is attributed to 2 redundant nuclear localization sequences in its L domain. Furthermore, the amphioxus IGFBP N-terminal domain has strong transcriptional activation activity. Forced expression of amphioxus IGFBP in zebrafish embryos results in dorsalized phenotypes. This action requires nuclear localization. These results suggest that the nuclear localization and transcription activation activity of IGFBPs are ancient functions and the IGF-binding function may have been acquired by opportunistic gain-of-functional mutations later in evolution.; IGFs play key roles in regulating vertebrate development, growth, reproduction, and aging. In extracellular fluids, IGFs are bound and regulated by a family of IGF-binding proteins (IGFBPs). Although all known IGFBPs are secreted proteins, some are also found in the nucleus and possess IGF-independent activities. When and how these distinct modes of biological actions have evolved is unknown. In this study, we identified and analyzed an IGFBP gene from amphioxus. Amphioxus shares a common ancestor with the modern vertebrate lineage that dates back to more than 520 million years ago. The amphioxus IGFBP shares all major structural characteristics of vertebrate IGFBPs. Phylogenetic analyses place it in a basal position in the IGFBP lineage. Ligand blot analysis reveals that amphioxus IGFBP does not bind to IGF-I or -II. Changing its Phe70 into Leu, however, is sufficient to convert it into a functional IGF binder. When tested in cultured cells, amphioxus IGFBP is localized in the nucleus, and this is attributed to 2 redundant nuclear localization sequences in its L domain. Furthermore, the amphioxus IGFBP N-terminal domain has strong transcriptional activation activity. Forced expression of amphioxus IGFBP in zebrafish embryos results in dorsalized phenotypes. This action requires nuclear localization. These results suggest that the nuclear localization and transcription activation activity of IGFBPs are ancient functions and the IGF-binding function may have been acquired by opportunistic gain-of-functional mutations later in evolution.
学科领域	Endocrinology & Metabolism
DOI	10.1210/en.2013-1201
URL	查看原文
收录类别	SCI
语种	英语
WOS研究方向	Endocrinology & Metabolism
WOS类目	Endocrinology & Metabolism
WOS记录号	WOS:000324759600028
WOS关键词	FACTOR BINDING PROTEIN-6 ; INSULIN-RECEPTOR FAMILY ; AMINO-ACIDS ; TRANSACTIVATION ACTIVITY ; NUCLEAR-LOCALIZATION ; CANCER CELLS ; EXPRESSION ; EVOLUTION ; ZEBRAFISH ; GENOME
WOS标题词	Science & Technology ; Life Sciences & Biomedicine
引用统计	被引频次：16[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://ir.qdio.ac.cn/handle/337002/16679
专题	实验海洋生物学重点实验室
通讯作者	Duan, CM
作者单位	1.Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA 2.Ocean Univ China, Minist Educ, Key Lab Marine Drugs, Qingdao 266003, Peoples R China 3.Ocean Univ China, Sch Med & Pharm, Qingdao 266003, Peoples R China 4.Ocean Univ China, Inst Evolut & Marine Biodivers, Qingdao 266003, Peoples R China 5.Chinese Acad Sci, Inst Oceanol, Key Lab Expt Marine Biol, Qingdao 266071, Peoples R China
推荐引用方式 GB/T 7714	Zhou, Jianfeng,Xiang, Jianhai,Zhang, Shicui,et al. Structural and Functional Analysis of the Amphioxus IGFBP Gene Uncovers Ancient Origin of IGF-Independent Functions[J]. ENDOCRINOLOGY,2013,154(10):3753-3763.
APA	Zhou, Jianfeng,Xiang, Jianhai,Zhang, Shicui,Duan, Cunming,&Duan, CM.(2013).Structural and Functional Analysis of the Amphioxus IGFBP Gene Uncovers Ancient Origin of IGF-Independent Functions.ENDOCRINOLOGY,154(10),3753-3763.
MLA	Zhou, Jianfeng,et al."Structural and Functional Analysis of the Amphioxus IGFBP Gene Uncovers Ancient Origin of IGF-Independent Functions".ENDOCRINOLOGY 154.10(2013):3753-3763.

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