Insulin-like Growth Factor-binding Protein-5 (IGFBP-5) Stimulates Growth and IGF-I Secretion in Human Intestinal Smooth Muscle by Ras-dependent Activation of p38 MAP Kinase and Erk1/2 Pathways

Kuemmerle, John F.; Zhou, Huiping

doi:10.1074/jbc.m200885200

Cited by 64 publications

(84 citation statements)

References 43 publications

(61 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…22,25 In these cells, IG-FBP-5 activates p38 kinase and p44/p42 MAPK. 22,25 Our results suggest that IGFBP-5 exerts its fibrotic effects on fibroblasts through MAPK activation, independently of IGF-I. Thus, MAPK activation by IGFBP-5 can now be added to the list of IGF-I-independent IGFBP-5 effects, which include stimulation of growth and IGF-I secretion by human intestinal smooth muscle cells, 22 migration of porcine vascular smooth muscle cells, 21 proliferation and activation of osteoblasts 28 -29 and osteoclasts, 30 and more recently induction of cellular senescence 31 and formation of hair shaft medulla.…”

Section: Discussionmentioning

confidence: 99%

“…22,25 To examine the effect of IGFBP-5 on intracellular signaling in primary human lung fibroblasts, we examined MAPK activation. As shown in Figure 1A, IGFBP-5 stimulates MAPK signaling as early as 5 minutes, peaks at 10 minutes, and then gradually decreases.…”

Section: Igfbp-5 Activates the Mapk Pathway In Primary Human Lung Fibmentioning

confidence: 99%

“…The IGF-I-independent effects of IGFBP-5 are significant and include migration of vascular smooth muscle cells and stimulation of growth and IGF-I secretion by human intestinal muscle cells. [21][22] There is evidence that IGFBP-5 binds to a receptor on the surface of fibroblasts that likely mediates its IGF-I-independent effects. However, this putative receptor has not yet been identified.…”

mentioning

confidence: 99%

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The Fibrotic Phenotype Induced by IGFBP-5 Is Regulated by MAPK Activation and Egr-1-Dependent and -Independent Mechanisms

Yasuoka

Hsu

Ruiz

et al. 2009

The American Journal of Pathology

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We have previously shown that insulin-like growth factor (IGF) binding protein-5 (IGFBP-5) is overexpressed in lung fibrosis and induces the production of extracellular matrix components, such as collagen and fibronectin, both in vitro and in vivo. The exact mechanism by which IGFBP-5 exerts these novel fibrotic effects is unknown. We thus examined the signaling cascades that mediate IGFBP-5-induced fibrosis. We demonstrate for the first time that

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Igfbp-5 Activates the Mapk Pathway In Primary Human Lung Fibmentioning

confidence: 99%

mentioning

confidence: 99%

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The Fibrotic Phenotype Induced by IGFBP-5 Is Regulated by MAPK Activation and Egr-1-Dependent and -Independent Mechanisms

Yasuoka

Hsu

Ruiz

et al. 2009

The American Journal of Pathology

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“…In human intestinal smooth muscle cells, the proliferative effect of IGFBP-5 depends on the Ras-dependent activation of p38 MAP-Kinase and the ERK1/2 pathways. 13 A decrease in IGFBP-5 gene expression following growth inhibition of the rat mammary gland has been reported. 14 On the contrary, during the involution of the mammary gland IGFBP-5 acts as inhibitory factor.…”

Section: Introductionmentioning

confidence: 99%

Silencing of endogenous IGFBP-5 by micro RNA interference affects proliferation, apoptosis and differentiation of neuroblastoma cells

et al. 2004

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Signal transduction through the IGF axis is implicated in proliferation, differentiation and survival during development and adult life. The IGF axis includes the IGF binding proteins (IGFBPs) that bind IGFs with high affinity and modulate their activity. In neuroblastoma (NB), a malignant childhood tumor, we found that IGFBP-5 is frequently expressed. Since NB is an IGF2-sensitive tumor, we investigated the relevance and the function of endogenous IGFBP-5 in LAN-5 and in SY5Y(N) cell lines transfected with micro and small interfering RNAs directed to IGFBP-5 mRNA. Cells in which IGFBP-5 expression was suppressed were growth-inhibited and more prone to apoptosis than the parental cell line and controls. Apoptosis was further enhanced by X-ray irradiation. The ability of these cells to undergo neuronal differentiation was impaired after IGFBP-5 inhibition but the effect was reversed by exposure to recombinant IGFBP-5. Together, these data demonstrate the importance of IGFBP-5 for NB cell functions and suggest that IGFBP-5 might serve as a novel therapeutic target in NB.

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Endogenous IGFBP-3 regulates excess collagen expression in intestinal smooth muscle cells of Crohnʼs disease strictures

Flynn

Mahavadi

Murthy

et al. 2011

Inflammatory Bowel Diseases

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Background Stricture formation occurs in ≈30% of patients with Crohn’s disease (CD) and is a significant cause of morbidity. Strictures are characterized by intestinal smooth muscle cell hyperplasia, smooth muscle cell hypertrophy, and fibrosis due to excess net extracellular matrix production, including collagen. Transforming growth factor-β1 (TGF-β1) has profibrotic effects in many tissues due to its ability to regulate collagen expression and extracellular matrix dynamics. We previously showed that both insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) and TGF-β1 are expressed by normal human intestinal smooth muscle cells, bind to, and activate TGF-βRII/I receptors in these cells. Methods Smooth muscle cells isolated from the muscularis propria of patients were used to prepare RNA, protein lysates, or placed into primary culture. IGFBP-3, TGF-β1, and collagen IαI expression was measured with quantitative reverse-transcription polymerase chain reaction (RT-PCR) and protein levels by enzyme-linked immunosorbent assay (ELISA) or immunoblot. Results Expression and production of IGFBP-3, TGF-β1, and collagen IαI were significantly increased specifically in smooth muscle cells isolated from regions of strictured intestine in CD compared to nonstrictured histologically normal resection margin. IGFBP-3 and TGF-β1 regulated collagen IαI expression and production via a TGF-βRII/I-dependent and Smad2/3-dependent mechanism. Upregulated (excess) collagen IαI expression and production in smooth muscle cells of strictures and basal collagen IαI in smooth muscle cells of normal margin were inhibited by immunoneutralization of IGFBP-3 or TGF-β1. Conclusions The findings indicate that upregulated endogenous IGFBP-3 and TGF-β1 expression regulates excess collagen IαI production and contributes to fibrosis and stricture formation in CD.

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Insulin-like Growth Factor-binding Protein-5 (IGFBP-5) Stimulates Growth and IGF-I Secretion in Human Intestinal Smooth Muscle by Ras-dependent Activation of p38 MAP Kinase and Erk1/2 Pathways

Cited by 64 publications

References 43 publications

The Fibrotic Phenotype Induced by IGFBP-5 Is Regulated by MAPK Activation and Egr-1-Dependent and -Independent Mechanisms

The Fibrotic Phenotype Induced by IGFBP-5 Is Regulated by MAPK Activation and Egr-1-Dependent and -Independent Mechanisms

Silencing of endogenous IGFBP-5 by micro RNA interference affects proliferation, apoptosis and differentiation of neuroblastoma cells

Endogenous IGFBP-3 regulates excess collagen expression in intestinal smooth muscle cells of Crohnʼs disease strictures

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