Nuclear localization signal in insulin-like growth factor-binding protein type 3

Radulescu, Razvan T.

doi:10.1016/0968-0004(94)90004-3

Cited by 76 publications

(43 citation statements)

References 11 publications

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“…Nuclear localisation Potential nuclear localisation signals are present in IGFBP-3 and -5 (Radulescu 1994). Consistent with this was the finding that recombinant IGFBP-3 and -5, but not IGFBP-1 and -2 are translocated to the nucleus of human breast cancer cells (Schedlich et al 1998).…”

Section: Binding To Cell Membrane Proteinssupporting

confidence: 71%

IGF-binding protein-5: flexible player in the IGF system and effector on its own

Schneider¹,

Wolf²,

Hoeflich³

et al. 2002

Journal of Endocrinology

162

137

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The multiple activities of IGF-I and -II are modulated by a family of IGF-binding proteins (IGFBP-1 to -6). Although structurally related, each IGFBP has unique properties and exerts specific functions. IGFBP-5 is the most conserved IGFBP across species and was identified as an essential regulator of physiological processes in bone, kidney and mammary gland. In addition, IGFBP-5 appears to play a decisive role in the control of proliferation of specific tumour cell types. In many situations IGFBP-5 exerts biological activities in the absence of IGFs, indicating the existence of IGF-independent actions. This concept was supported by the unexpected localisation of IGFBP-5 in the nucleus and the description of IGFBP-5-specific membrane-bound IGFBP-5 receptor(s). The scope of this review is to summarise the available information about the structure of IGFBP-5 and the regulation of its expression. Furthermore, the potential significance of IGFBP-5 in the regulation of physiological processes will be critically analysed in the light of recent experimental data.

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Section: Binding To Cell Membrane Proteinssupporting

confidence: 71%

IGF-binding protein-5: flexible player in the IGF system and effector on its own

Schneider¹,

Wolf²,

Hoeflich³

et al. 2002

Journal of Endocrinology

162

137

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show abstract

“…Likewise, a peptide corresponding to the nuclear localization sequence of IGFBP-5 (residues 201-218) fused to enhanced green fluorescent protein and transfected into Chinese hamster ovary cells targeted enhanced green fluorescent protein to the nucleus (14). These experimental observations are consistent with the presence of a consensus nuclear localization sequence in IGFBP-5 and IGFBP-3 (15). It has also been reported that IGFBP-5 may interact with Four and a Half LIM protein 2 (FHL2) and retinoid X receptor, nuclear proteins known to be involved in transcriptional regulation (16,17).…”

supporting

confidence: 72%

Several Acidic Amino Acids in the N-domain of Insulin-like Growth Factor-binding Protein-5 Are Important for Its Transactivation Activity

Zhao

Yin

Bach

et al. 2006

Journal of Biological Chemistry

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Insulin-like growth factor-binding protein (IGFBP)-5 is a secreted protein that binds to IGFs and modulates IGF actions. IGFBP-5 is also found in the nuclei of cultured cells and has transactivation activity.Here we report the nuclear localization of endogenous IGFBP-5 in mouse embryonic skeletal cells. Chromatin immunoprecipitation experiments indicated that IGFBP-5 interacts with the nuclear histone-DNA complex. Using a series of deletion mutants, the transactivation domain of IGFBP-5 was mapped to its N-terminal region. Intriguingly, the transactivation activity of IGFBP-5 is masked by negative regulatory elements located in the L-and C-domains. Among the other IGFBPs, the N-domains of IGFBP-2 and -3 also had strong transactivation activity, whereas those of IGFBP-1 and -6 had no activity. The IGFBP-4 N-domain had modest activity. Sequence analysis revealed several amino acids in the IGFBP-5 N-domain that are not present in IGFBP-1. The activities of mutants in which these residues were changed to the corresponding IGFBP-1 sequence were determined. Mutations that changed acidic residues to neutral residues (e.g. E8A, D11S, E12A, E30S/P31A, E43L, and E52A) or a polar to a basic residue (e.g. Q56R) significantly reduced transactivation activity. The E8A/D11S/E12A triple mutant and E52A/Q56R double mutants showed further reduced activity. The combinatory mutants had essentially no transactivation activity. Taken together, our results indicate that there are several conserved residues in the IGFBP-5 N-terminal region that are critical for transactivation and that IGFBP-2 and -3 also have strong transactivation activity in their N-domains.The insulin-like growth factor (IGF) 2 system, consisting of two ligands (IGF-I and -II), two receptors (the IGF-I receptor and IGF-II receptor), and six high affinity IGF-binding proteins (IGFBPs), converges on a conserved signaling pathway that plays fundamental roles in vertebrate development and physiology and is implicated in several human diseases (1). The bioavailability and bioactivity of IGFs are regulated by their interactions with various members of the IGFBP family. IGFBPs all have a highly cysteine-rich N-terminal (N)-domain, a cysteine-rich C-terminal (C)-domain, and a middle linker (L)-domain with no cysteine residues except in IGFBP-4. The N-and C-domains are highly conserved within the IGFBP family, whereas the L-domain varies both within the family and across species.Besides binding to IGF and modulating its actions, IGFBP-5 has been reported to regulate cell proliferation (2, 3), migration (4 -6), and apoptosis/survival (7-11) independent of IGF. Although the ligand-dependent actions of IGFBP-5 are attributed to its interactions with the IGF ligand and other proteins (1), the mechanistic basis of the ligand-independent actions of IGFBP-5 is not yet understood.Andress et al. (12) used IGFBP-5 affinity chromatography to purify a 420-kDa membrane protein from human osteoblast cells and proposed that it was an IGFBP-5 receptor. The same study reported that IGFBP-5 ...

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“…Significantly, in the context of IGF-independent nuclear action, the C-terminal regions of IGFBP-3 and IGFBP-5 contain a domain with strong sequence homology to the bipartite NLS consensus motif (29). This basic domain is highly conserved in IGFBP-3 and IGFBP-5 from different species, suggesting that it has functional significance.…”

Section: Are Modulated By a Family Of Igf-binding Proteins (Igfbps)mentioning

confidence: 99%

Nuclear Import of Insulin-like Growth Factor-binding Protein-3 and -5 Is Mediated by the Importin β Subunit

Schedlich

Page

Firth

et al. 2000

Journal of Biological Chemistry

266

224

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Nuclear localization signal in insulin-like growth factor-binding protein type 3

Cited by 76 publications

References 11 publications

IGF-binding protein-5: flexible player in the IGF system and effector on its own

IGF-binding protein-5: flexible player in the IGF system and effector on its own

Several Acidic Amino Acids in the N-domain of Insulin-like Growth Factor-binding Protein-5 Are Important for Its Transactivation Activity

Nuclear Import of Insulin-like Growth Factor-binding Protein-3 and -5 Is Mediated by the Importin β Subunit

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