Synergy between PI3K/Akt and Raf/MEK/ERK Pathways in IGF-1R Mediated Cell Cycle Progression and Prevention of Apoptosis in Hematopoietic Cells

Shelton, John G.; Steelman, Linda S.; White, Edmond R.; McCubrey, James A.

doi:10.4161/cc.3.3.747

Cited by 96 publications

(93 citation statements)

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“…The PI3K pathway has been shown to interact with the ERK1/2 pathway in some cells (39,40), including in human ECs (26), and several possible molecular intermediates have been shown to facilitate cross-talk between the PI3K-and ERK-signaling pathways (33). The potential role of Lnk at the signaling intersection between PI3K and ERK (MAPK) and the cross-talk between the two kinases needs further investigation and may be of great significance in the understanding of vascular biology.…”

Section: Discussionmentioning

confidence: 99%

The Adaptor Molecule Lnk Negatively Regulates Tumor Necrosis Factor-α-dependent VCAM-1 Expression in Endothelial Cells through Inhibition of the ERK1 and -2 Pathways

Fitau¹,

Boulday²,

Coulon³

et al. 2006

Journal of Biological Chemistry

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Lnk, with APS and SH2-B (Src homology 2-B), belongs to a family of SH2-containing proteins with potential adaptor functions. Lnk regulates growth factor and cytokine receptor-mediated pathways implicated in lymphoid, myeloid, and platelet homeostasis. We have previously shown that Lnk is expressed and up-regulated in vascular endothelial cells (ECs) in response to tumor necrosis factor-␣ (TNF␣). In this study, we have shown that, in ECs, Lnk down-regulates the expression, at both mRNA and protein levels, of the proinflammatory molecules VCAM-1 and E-selectin induced by TNF␣. Mechanistically, our data indicated that, in response to TNF␣, NFB/p65 phosphorylation and translocation as well as IB␣ phosphorylation and degradation were unchanged, suggesting that Lnk does not modulate NFB activity. However, Lnk activates phosphatidylinositol 3-kinase (PI3K) as reflected by Akt phosphorylation. Our results identify endothelial nitric-oxide synthase as a downstream target of Lnk-mediated activation of the PI3K/Akt pathway and HO-1 as a new substrate of Akt. We found that sustained Lnkmediated activation of PI3K in TNF␣-activated ECs correlated with the inhibition of ERK1/2 phosphorylation, whereas phosphorylation of p38 and c-Jun NH 2 -terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) was unchanged. ERK1/2 inhibition decreases VCAM-1 expression in TNF␣-treated ECs. Collectively, our results identify the adaptor Lnk as a negative regulator in the TNF␣-signaling pathway mediating ERK inhibition and suggest a role for Lnk in the interplay between PI3K and ERK triggered by TNF␣ in ECs.

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Section: Discussionmentioning

confidence: 99%

The Adaptor Molecule Lnk Negatively Regulates Tumor Necrosis Factor-α-dependent VCAM-1 Expression in Endothelial Cells through Inhibition of the ERK1 and -2 Pathways

Fitau¹,

Boulday²,

Coulon³

et al. 2006

Journal of Biological Chemistry

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“…Whether oral IGF1 affects somatic tissue development beyond the gastrointestinal (GI) tract is unknown. IGF1 signaling can act via the phosphatidylinositol-3 kinase (PI3K)/AKT pathway (Tseng et al 2002, Shelton et al 2004 to promote cell proliferation, differentiation, and survival (Baserga & Rubin 1993). A serine/threonine kinase (Shelton et al 2004), AKT, activated when phosphorylated AKT (pAKT), increases the levels of the anti-apoptotic protein B-cell lymphoma 2 (BCL2) (Mora et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Effects of age, nursing, and oral IGF1 supplementation on neonatal porcine cervical development

Camp¹,

Wiley²,

Boulos³

et al. 2014

Reproduction

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Nursing supports neonatal porcine uterine and testicular development, however, lactocrine effects on cervical development are undefined. Studies were conducted to determine the effects of i) age and the imposition of the lactocrine-null state from birth (postnatal day 0 (PND0)) by milk replacer feeding on cervical histology; ii) imposition of the lactocrine-null state for 2 days from birth on cervical cell proliferation, as reflected by proliferating cell nuclear antigen immunostaining; and iii) a single feeding of colostrum or milk replacer, administered at birth, with or without oral IGF1, on cervical cell proliferation and phosphorylated AKT (pAKT) and B-cell lymphoma 2 (BCL2) protein levels at 12 h postnatal. Cervical crypt depth and height of luminal epithelium (LE) increased with age by PND14, when both responses were reduced in replacer-fed gilts. Cell proliferation was reduced in LE at PND2, and in crypt epithelium and stroma by PND14 in replacer-fed gilts. Returning replacer-fed gilts to nursing on PND2 did not rescue the cervical phenotype by PND14. A single feeding of colostrum, but not milk replacer, was sufficient to support cervical cell proliferation at 12 h postnatal. IGF1 supplementation induced cell proliferation in replacer-fed gilts, and increased cervical pAKT and BCL2 levels in colostrum-fed gilts and replacer-fed gilts at 12 h postnatal. Results indicate that age and nursing support porcine cervical development, support is initiated at first ingestion of colostrum, IGF1 may be lactocrine-active, and identification of lactocrine-active factors can be accomplished by 12 h postnatal using this bioassay system.

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“…Because IGF1R signaling prevents apoptosis through the PI3K-AKT pathway [19] , we next wanted to address whether hematoxylin induces apoptosis in HL-60 cells.…”

Section: Hematoxylin Induces Apoptosis In Hl-60 Cellsmentioning

confidence: 99%

Establishment of platform for screening insulin-like growth factor-1 receptor inhibitors and evaluation of novel inhibitors

et al. 2011

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Aim: The insulin-like growth factor-1 receptor (IGF1R) is over-expressed in a wide variety of tumors and contributes to tumor cell proliferation, metastasis and drug resistance. The aim of this study was to establish a sensitive screening platform to identify novel IGF1R inhibitors. Methods: The catalytic domain of IGF1R was expressed using the Bac-to-Bac baculovirus expression system. The screening platform for IGF1R inhibitors was established based on ELISA. The binding profile of IGF1R with the inhibitors was predicted with molecular docking and then subjected to the surface plasmon resonance (SPR) approach. The growth inhibition of cancer cells by the inhibitors was assessed with MTT assay. Apoptosis was analyzed using flow cytometry and Western blotting. Results: A naturally occurring small molecule compound hematoxylin was identified as the most potent inhibitor (IC 50 value=1.8±0.1 μmol/L) within a library of more than 200 compounds tested. Molecular simulation predicted the possible binding mode of hematoxylin with IGF1R. An SPR assay further confirmed that hematoxylin bound directly to IGF1R with high binding affinity (Kd=4.2×10 -6 mol/L). In HL-60 cancer cells, hematoxylin inactivated the phosphorylation of IGF1R and downstream signaling and therefore suppressed cell proliferation. Mechanistic studies revealed that hematoxylin induced apoptosis in HL-60 cells via both extrinsic and intrinsic pathways. Conclusion: A simple, sensitive ELISA-based screening platform for identifying IGF1R inhibitors was established. Hematoxylin was identified as a promising IGF1R inhibitor with effective antitumor activity that deserves further investigation.

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Synergy between PI3K/Akt and Raf/MEK/ERK Pathways in IGF-1R Mediated Cell Cycle Progression and Prevention of Apoptosis in Hematopoietic Cells

Cited by 96 publications

References 0 publications

The Adaptor Molecule Lnk Negatively Regulates Tumor Necrosis Factor-α-dependent VCAM-1 Expression in Endothelial Cells through Inhibition of the ERK1 and -2 Pathways

The Adaptor Molecule Lnk Negatively Regulates Tumor Necrosis Factor-α-dependent VCAM-1 Expression in Endothelial Cells through Inhibition of the ERK1 and -2 Pathways

Effects of age, nursing, and oral IGF1 supplementation on neonatal porcine cervical development

Establishment of platform for screening insulin-like growth factor-1 receptor inhibitors and evaluation of novel inhibitors

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