Characterization of IRA/IRB hybrid insulin receptors using bioluminescence resonance energy transfer

Blanquart, Christophe; Achi, Josepha; Issad, Tarik

doi:10.1016/j.bcp.2008.07.027

Cited by 56 publications

(41 citation statements)

References 29 publications

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“…The M and Rr coefficients were similar to those calculated when the same isoform was coexpressed fused to the VFPs SCFP and SYFP. These results are in agreement with previous reports demonstrating (or assuming) the existence of IR-A and IR-B heterodimers Benyoucef et al, 2007;Blanquart et al, 2008). By contrast, Uhles et al (Uhles et al, 2003) reported experiments on pancreatic beta cells using fluorescence resonance energy transfer, according to which IR isoforms localized to different membrane domains, abrogating the formation of heterodimers and promoting isoformspecific IR signaling.…”

Section: Discussionsupporting

confidence: 92%

Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B

Giudice

Leskow

Arndt‐Jovin

et al. 2011

Journal of Cell Science

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Insulin signaling comprises a complex cascade of events, playing a key role in the regulation of glucose metabolism and cellular growth. Impaired response to insulin is the hallmark of diabetes, whereas upregulated insulin activity occurs in many cancers. Two splice variants of the insulin receptor (IR) exist in mammals: IR-A, lacking exon 11, and full-length IR-B. Although considerable biochemical data exist on insulin binding and downstream signaling, little is known about the dynamics of the IR itself. We created functional IR transgenes fused with visible fluorescent proteins for use in combination with biotinamido-caproyl insulin and streptavidin quantum dots. Using confocal and structured illumination microscopy, we visualized the endocytosis of both isoforms in living and fixed cells and demonstrated a higher rate of endocytosis of IR-A than IR-B. These differences correlated with higher and sustained activation of IR-A in response to insulin and with distinctive ERK1/2 activation profiles and gene transcription regulation. In addition, cells expressing IR-B showed higher AKT phosphorylation after insulin stimulation than cells expressing IR-A. Taken together, these results suggest that IR signaling is dependent on localization; internalized IRs regulate mitogenic activity, whereas metabolic balance signaling occurs at the cell membrane.

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Section: Discussionsupporting

confidence: 92%

Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B

Giudice

Leskow

Arndt‐Jovin

et al. 2011

Journal of Cell Science

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show abstract

“…Thus, it is reasonable to assume that HCC tumors express more frequently a mixture of IR-A/IR-A and IR-A/IR-B dimers. Both dimers can bind insulin with high affinity and stimulate cell proliferation and survival (34). Receptor dimers engaging IR-A can also bind the mitogen IGF-II with a high affinity.…”

Section: Discussionmentioning

confidence: 99%

Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors

et al. 2013

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Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of IR pre-mRNA is dysregulated in a panel of 85 human hepatocellular carcinoma (HCC) while being normal in adjacent nontumor liver tissue. An IR-B to IR-A switch is frequently observed in HCC tumors regardless of tumor etiology. Using pharmacologic and siRNA approaches, we show that the autocrine or paracrine activation of the EGF receptor (EGFR)/mitogen-activated protein/extracellular signal-regulated kinase pathway increases the IR-A:IR-B ratio in HCC cell lines, but not in normal hepatocytes, by upregulating the expression of the splicing factors CUGBP1, hnRNPH, hnRNPA1, hnRNPA2B1, and SF2/ASF. In HCC tumors, there is a significant correlation between the expression of IR-A and that of splicing factors. Dysregulation of IR pre-mRNA splicing was confirmed in a chemically induced model of HCC in rat but not in regenerating livers after partial hepatectomy. This study identifies a mechanism responsible for the generation of mitogenic IR-A and provides a novel interplay between IR and EGFR pathways in HCC. Increased expression of IR-A during neoplastic transformation of hepatocytes could mediate some of the adverse effects of hyperinsulinemia on HCC. Cancer Res; 73(13); 3974-86. Ó2013 AACR.

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“…The hybrid receptors, IR-A/IR-B and IR/IGF-I further complicates the molecular diversification of the insulin signaling system. IR-A/IR-B hybrid receptors were found to bind to both insulin and IGF-II and therefore, resemble IR-A homodimers rather IR-B homodimers (Blanquart et al, 2008). The IR/IGF-IR hybrid receptors (Pandini et al, 2002;Soos et al, 1990) are activated by both insulin as well as IGF-I, but the IGF-I effect is predominant, and it resembles IGF-1R homodimers rather IR homodimers (Langlois et al, 1995).…”

Section: Hyperinsulinemia: Altered Insulin/igf Signalingmentioning

confidence: 99%

Lipids in the Pathogenesis of Benign Prostatic Hyperplasia: Emerging Connections

Vikram¹,

Ramarao²

2012

Dyslipidemia - From Prevention to Treatment

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Characterization of IRA/IRB hybrid insulin receptors using bioluminescence resonance energy transfer

Cited by 56 publications

References 29 publications

Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B

Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B

Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors

Lipids in the Pathogenesis of Benign Prostatic Hyperplasia: Emerging Connections

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