Insulin-like Growth Factor-binding Protein-3 Activates a Phosphotyrosine Phosphatase

Ricort, Jean‐Marc; Binoux, M

doi:10.1074/jbc.m200439200

Cited by 56 publications

(51 citation statements)

References 29 publications

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“…The IGFBP-3 NLS mutant, which is known to not translocate to the nucleus, also inhibited insulin-stimulated glucose uptake (13) Thus, it is possible that some of the insulin-antagonistic effects of IG-FBP-3 are mediated via IGF-independent pathways that does not require nuclear localization. For example, a previously published study reports that IGFBP-3 is capable of activating a phosphotyrosine phosphatase independent of its IGF binding affinity (29). Activation of a phosphotyrosine phosphatase and subsequent de-phosphorylation could be a mechanism responsible for the decreased phosphorylated insulin receptor levels observed in our study.…”

Section: Discussionmentioning

confidence: 51%

Insulin-Like Growth Factor Binding Protein-3 Induces Insulin Resistance in Adipocytes In Vitro and in Rats In Vivo

et al. 2007

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Insulin-like growth factor binding protein (IGFBP)-3 binds to IGF and modulates their actions and also possesses intrinsic activities. We investigated its effects on insulin action and found that when IGFBP-3 was added to fully differentiated 3T3-L1 adipocytes in culture, insulin-stimulated glucose transport was significantly inhibited to 60% of control in a time-and dose-dependent manner. Tumor necrosis factor (TNF)-␣ treatment also inhibited glucose transport to the same degree as IGFBP-3 and, in addition, increased IGFBP-3 levels 3-fold. Co-treatment with TNF-␣ and IGFBP-3 antisense partially prevented the inhibitory effect of TNF-␣ on glucose transport, indicating a role for IGFBP-3 in cytokine-induced insulin resistance. Insulin-stimulated phosphorylation of the insulin receptor was markedly decreased by IGFBP-3 treatment. IGFBP-3 treatment suppressed adiponectin expression in 3T3-L1 adipocytes. Infusion of IGFBP-3 to Sprague-Dawley rats for 3 h decreased peripheral glucose uptake by 15% compared with controls as well as inhibiting glycogen synthesis. Systemic administration of IGFBP-3 to rats for 7 d resulted in a dramatic 40% decrease in peripheral glucose utilization and glycogen synthesis. These in vitro and in vivo findings demonstrate that IGFBP-3 has potent insulin-antagonizing capability and suggest a role for IGFBP-3 in cytokine-induced insulin resistance and other mechanisms involved in the development of type-2 diabetes. (Pediatr Res 61: 159-164, 2007)

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Section: Discussionmentioning

confidence: 51%

Insulin-Like Growth Factor Binding Protein-3 Induces Insulin Resistance in Adipocytes In Vitro and in Rats In Vivo

et al. 2007

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“…This protein was subsequently determined to be identical to the low density lipoprotein receptor-related protein LRP1, also known as the α2-macroglobulin receptor, and its mediation of IGFBP-3 growth-inhibitory signaling was said to involve the dephosphorylation of insulin receptor substrate-2 (IRS-2) (Huang, et al 2004). Another, unrelated report also described an inhibitory role for IGFBP-3 mediated through protein dephosphorylation (Ricort and Binoux 2002).…”

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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“…34 One explanation for the overexpression of IGFBP-3 in malignancies is that IGFBP-3 may inhibit tumor cell proliferation via a negative feedback mechanism. 37,[39][40][41][42] Another possibility is that unknown defects in IGFBP-3 receptor function may lead to IGFBP-3 overexpression in these tumors. 22 Overall, the expression and function of IGFBP-3 may differ according to the type of malignancy.…”

Section: Discussionmentioning

confidence: 99%

Aberrant promoter methylation of insulin‐like growth factor binding protein‐3 gene in human cancers

Tomii

Tsukuda

Toyooka

et al. 2006

Intl Journal of Cancer

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Insulin-like growth factor binding protein-3 (IGFBP-3) is postulated to be a mediator of growth suppression signals. Here, we examined the methylation status of IGFBP-3 to correlate to clinicopathological factors in human cancers. The methylation status of IGFBP-3 was determined by bisulfite DNA sequencing and was correlated with expression semi-quantified by real-time RT-PCR to develop a methylation-specific PCR (MSP) assay for IGFBP-3. Using the MSP assay, we examined the methylation status of IGFBP-3 in gastric cancer (GC), colorectal cancer (CRC), breast cancer (BC) and malignant mesothelioma (MM). IGFBP-3 methylation was detected in 6 of 13 (46%) and 16 of 24 (67%) GC cell lines and tumors, respectively; 4 of 8 (50%) and 15 of 26 (58%) CRC cell lines and tumors, respectively; 3 of 11 (27%) and 7 of 39 (18%) BC cell lines and tumors, respectively and 1 of 5 (20%) and 18 of 56 (32%) MM cell lines and tumors, respectively. Interestingly, the methylation status of MM specimens from Japanese patients (75%, 12 out of 16 patients) was significantly higher than those from the USA (15%, 6 out of 40 patients) (p < 0.0001), suggesting the presence of ethnic differences in the IGFBP-3 methylation status. We also found that IGFBP-3 methylation was preferentially present in GCs arising in the lower-third of the stomach (p 5 0.079). In summary, our results showed that IGFBP-3 methylation played an important role in the silencing of its expression, suggesting that IGFBP-3 may act as a tumor suppressor gene in several human cancers examined. ' 2006 Wiley-Liss, Inc.

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Insulin-like Growth Factor-binding Protein-3 Activates a Phosphotyrosine Phosphatase

Cited by 56 publications

References 29 publications

Insulin-Like Growth Factor Binding Protein-3 Induces Insulin Resistance in Adipocytes In Vitro and in Rats In Vivo

Insulin-Like Growth Factor Binding Protein-3 Induces Insulin Resistance in Adipocytes In Vitro and in Rats In Vivo

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

Aberrant promoter methylation of insulin‐like growth factor binding protein‐3 gene in human cancers

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