Insulin-like Growth Factor-independent Effects Mediated by a C-terminal Metal-binding Domain of Insulin-like Growth Factor Binding Protein-3

Singh, Baljit; Charkowicz, Dona A; Mascarenhas, Desmond

doi:10.1074/jbc.m307322200

Cited by 60 publications

(66 citation statements)

References 49 publications

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“…Exogenous IGFBP-3 can be internalized (63,65) by clathrindependent endocytosis of IGFBP-3-transferrin complexes bound to the transferrin receptor (51) and by clathrin-independent endocytosis via lipid rafts (51,82). Based on studies with other ligands and their receptors, endocytosis may have diverse outcomes.…”

Section: Discussionmentioning

confidence: 99%

Nonsecreted Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Can Induce Apoptosis in Human Prostate Cancer Cells by IGF-independent Mechanisms without Being Concentrated in the Nucleus

Bhattacharyya

Pechhold

Shahjee

et al. 2006

Journal of Biological Chemistry

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Insulin-like growth factor binding protein-3 (IGFBP-3), a secreted protein, has the intrinsic ability to induce apoptosis directly without binding insulin-like growth factors. Previous studies suggested that IGFBP-3 must be secreted to exert its biological functions. IGFBP-3 contains a nuclear localization signal (NLS), and exogenous IGFBP-3 is translocated into the nucleus, suggesting that both secretion and nuclear localization may play important roles in IGFBP-3 action. To address these questions, we fused yellow fluorescent protein (YFP) to mature IGFBP-3 lacking its signal peptide so that it would remain intracellular and mutated the C-terminal NLS of IGFBP-3, 228 KGRKR 232 , to MDGEA. Following transfection of PC-3 human prostate cancer cells with these constructs, Western blots indicated that YFP-IGFBP-3 lacking a signal peptide was cell-associated and not present in the extracellular media. Moreover, the fusion protein was not N-glycosylated, indicating that it had not entered the secretory pathway. Confocal imaging showed that intracellular YFP-MDGEA-IGFBP-3 was predominantly cytoplasmic. Transient transfection of nonsecreted YFP-wild-type IGFBP-3 decreased cell viability, as assessed by staining with annexin V followed by flow cytometry. Induction of cell death was caspase-dependent, indicative of apoptosis. Apoptosis also was induced by the nonsecreted NLS mutant (YFP-MD-GEA-IGFBP-3) alone and when the IGF-binding site also had been mutated. These results indicate that IGFBP-3 can induce apoptosis in an IGF-independent manner without being secreted or concentrated in the nucleus.

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Section: Discussionmentioning

confidence: 99%

Nonsecreted Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Can Induce Apoptosis in Human Prostate Cancer Cells by IGF-independent Mechanisms without Being Concentrated in the Nucleus

Bhattacharyya

Pechhold

Shahjee

et al. 2006

Journal of Biological Chemistry

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“…Other studies found that IGFBP-3 endocytosis requires a caveolin-binding structural motif and involves its binding to transferrin and internalization through the transferrin receptor (Lee, et al 2004;Singh, et al 2004). Interactions with β 1 integrin and caveolin-1 have also been reported in other studies (Perks, et al 2011).…”

Section: Lrp1 and Tgfβ Signalingmentioning

confidence: 99%

Insulin-like growth factor binding protein-3 (IGFBP-3): Novel ligands mediate unexpected functions

Baxter

2013

J. Cell Commun. Signal.

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In addition to its important role in the regulation of somatic growth by acting as the major circulating transport protein for the insulin-like growth factors (IGFs), IGF binding protein-3 (IGFBP-3) has a variety of intracellular ligands that point to its function within major signaling pathways. The discovery of its interaction with the retinoid X receptor has led to the elucidation of roles in regulating the function of several nuclear hormone receptors including retinoic acid receptor-α, Nur77 and vitamin D receptor. Its interaction with the nuclear hormone receptor peroxisome proliferator-activated receptor-γ is believed to be involved in regulating adipocyte differentiation, which is also modulated by IGFBP-3 through an interaction with TGFβ/Smad signaling. IGFBP-3 can induce apoptosis alone or in conjunction with other agents, and in different systems can activate caspases −8 and −9. At least two unrelated proteins (LRP1 and TMEM219) have been designated as receptors for IGFBP-3, the latter with a demonstrated role in inducing caspase-8-dependent apoptosis. In contrast, IGFBP-3 also has demonstrated roles in survival-related functions, including the repair of DNA double-strand breaks through interaction with the epidermal growth factor receptor and DNAdependent protein kinase, and the induction of autophagy through interaction with GRP78. The ability of IGFBP-3 to modulate the balance between pro-apoptotic and prosurvival sphingolipids by regulating sphingosine kinase 1 and sphingomyelinases may be integral to its role at the crossroads between cell death and survival in response to a variety of stimuli. The pleiotropic nature of IGFBP-3 activity supports the idea that IGFBP-3 itself, or pathways with which it interacts, should be investigated as targets of therapy for a variety of diseases.

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“…The basic region, Lys228-Arg232, is essential for interaction with ALS (58), and additional basic residues are present that interact with the cell surface and matrix, the nuclear transporter importin-b (59), and other proteins. Moreover, this region contains a short metal-binding domain (60) and caveolinscaffolding domain consensus sequence (10).…”

Section: Igfbp-3 and Igfbp-3r Igfbp-3mentioning

confidence: 99%

Targeting Insulin-Like Growth Factor-I and Insulin-Like Growth Factor–Binding Protein-3 Signaling Pathways. A Novel Therapeutic Approach for Asthma

Lee

Kim

et al. 2014

Am J Respir Cell Mol Biol

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Insulin-like Growth Factor-independent Effects Mediated by a C-terminal Metal-binding Domain of Insulin-like Growth Factor Binding Protein-3

Cited by 60 publications

References 49 publications

Nonsecreted Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Can Induce Apoptosis in Human Prostate Cancer Cells by IGF-independent Mechanisms without Being Concentrated in the Nucleus

Nonsecreted Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Can Induce Apoptosis in Human Prostate Cancer Cells by IGF-independent Mechanisms without Being Concentrated in the Nucleus

Insulin-like growth factor binding protein-3 (IGFBP-3): Novel ligands mediate unexpected functions

Targeting Insulin-Like Growth Factor-I and Insulin-Like Growth Factor–Binding Protein-3 Signaling Pathways. A Novel Therapeutic Approach for Asthma

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