Evidence that IGF-binding protein-5 functions as a growth factor

Miyakoshi, Naohisa; Richman, Charmaine; Kasukawa, Yuji; Linkhart, Thomas A.; Baylink, David J.; Mohan, Subburaman

doi:10.1172/jci10459

Cited by 192 publications

(183 citation statements)

References 45 publications

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“…IGFBP5 is also expressed in many fetal, neonatal, and adult tissues and local IGFBP5 can modulate IGF activities in an autocrine/paracrine manner 15 or can have ligand-independent action. 35,36 In differentiating murine myoblasts, for example, IGFBP5 is located on the cell surface, and its expression is induced in the early stages during myogenesis. 37 The cell surface-associated IGFBP5 binds to IGF-2 and brings IGF-2 into close proximity of the IGF1R, thereby enhancing IGF1R-mediated PI3K-Akt signaling activity.…”

Section: Discussionmentioning

confidence: 99%

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

et al. 2013

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Calcium deficiency causes abnormal colonic growth and increases colon cancer risk with poorly understood mechanisms. Here we elucidate a novel signaling mechanism underlying the Ca 2 þ deficiency-induced epithelial proliferation using a unique animal model. The zebrafish larval yolk sac skin contains a group of Ca 2 þ -transporting epithelial cells known as ionocytes. Their number and density increases dramatically when acclimated to low [Ca 2 þ ] environments. BrdU pulse-labeling experiments suggest that low [Ca 2 þ ] stimulates pre-existing ionocytes to re-enter the cell cycle. Low [Ca 2 þ ] treatment results in a robust and sustained activation of IGF1R-PI3K-Akt signaling in these cells exclusively. These ionocytes specifically express Igfbp5a, a high-affinity and specific binding protein for insulin-like growth factors (IGFs) and the Ca 2 þ -selective channel Trpv5/6. Inhibition or knockdown of Igfbp5a, IGF1 receptor, PI3K, and Akt attenuates low [Ca 2 þ ]-induced ionocyte proliferation. The role of Trpv5/6 was investigated using a genetic mutant, targeted knockdown, and pharmacological inhibition. Loss-of-Trpv5/6 function or expression results in elevated pAkt levels and increased ionocyte proliferation under normal [Ca 2 þ ]. These increases are eliminated in the presence of an IGF1R inhibitor, suggesting that Trpv5/6 represses IGF1R-PI3K-Akt signaling under normal [Ca 2 þ ]. Intriguingly, blockade of Trpv5/6 activity inhibits the low [Ca 2 þ ]-induced activation of Akt. Mechanistic analyses reveal that the low [Ca 2 þ ]-induced IGF signaling is mediated through Trpv5/6-associated membrane depolarization. Low extracellular [Ca 2 þ ] results in a similar amplification of IGF-induced PI3K-PDK1-Akt signaling in human colon cancer cells in a TRPV6-dependent manner. These results uncover a novel and evolutionarily conserved signaling mechanism that contributes to the abnormal epithelial proliferation associated with Ca 2 þ deficiency.

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Section: Discussionmentioning

confidence: 99%

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

et al. 2013

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“…In conclusion, although our data confirm that IGF2 stimulates proliferation of NB cells, they suggest that endogenously produced IGFBP-5 acts, at least in part, via an IGF-independent mechanism, consistent with the effect of IGFBP-5 in stimulating proliferation of bone cells. 11 The activity of IGFBP-5 as a growth stimulatory protein was also demonstrated in smooth muscle cells. 41 On the contrary, the proliferation of mammary cells transfected or infected with vectors producing IGFBP-5 was inhibited.…”

Section: Discussionmentioning

confidence: 99%

“…11 We have previously reported that ectopic administration of recombinant IGFBP-5 (1-100 ng/ml) was able to induce a proliferative effect in NB cells. 27 Addition of 1 ng/ml of recombinant IGFBP-5 increased proliferation of IGFBP-5-interfered cells (clone I2B) to 11273.87 compared with 10073.79 of untreated cells (Figure 5a).…”

Section: Igfbp-5 Interference Causes Growth Inhibition Of Nb Cellsmentioning

confidence: 95%

“…In addition, IGFBP-5 has been demonstrated to function as IGF-independent cytokine in bone cells. 11 Intriguingly, the function of IGFBP-5 seems tissue-specific and dosage-dependent. In bone 11 and smooth muscle cells, 12 this protein promotes proliferation.…”

Section: Introductionmentioning

confidence: 99%

“…11 Intriguingly, the function of IGFBP-5 seems tissue-specific and dosage-dependent. In bone 11 and smooth muscle cells, 12 this protein promotes proliferation. 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.…”

Section: Introductionmentioning

confidence: 99%

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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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Biology of insulin‐like growth factors in development

Dupont¹,

Holzenberger²

2003

Birth Defects Research Pt C

177

140

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Insulin-like growth factors (IGFs) provide essential signals for the control of embryonic and postnatal development in vertebrate species. In mammals, IGFs act through and are regulated by a system of receptors, binding proteins, and related proteases. In each of the many tissues dependent on this family of growth factors, this system generates a complex interaction specific to the tissue concerned. Studies carried out over the last decade, mostly with transgenic and gene knockout mouse models, have demonstrated considerable variety in the cell type-specific and developmental stage-specific functions of IGF signals. Brain, muscle, bone, cartilage, pancreas, ovary, skin, and fat tissue have been identified as major in vivo targets for IGFs. Concentrating on several of these organ systems, we review here phenotypic analyses of mice with genetically modified IGF systems. Much progress has also been made in understanding the specific intracellular signaling cascades initiated by the binding of circulating IGFs to their cognate receptor. We also summarize the most relevant aspects of this research. Considerable efforts are currently focused on deciphering the functional specificities of intracellular pathways, particularly the molecular mechanisms by which cells distinguish growth-stimulating insulin-like signals from metabolic insulin signals. Finally, there is a growing body of evidence implicating IGF signaling in lifespan control, and it has recently been shown that this function has been conserved throughout evolution. Very rapid progress in this domain seems to indicate that longevity may be subject to IGF-dependent neuroendocrine regulation and that certain periods of the life cycle may be particularly important in the determination of individual lifespan.

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Evidence that IGF-binding protein-5 functions as a growth factor

Cited by 192 publications

References 45 publications

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

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

Biology of insulin‐like growth factors in development

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