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

Giudice, Jimena; Leskow, Federico Coluccio; Arndt‐Jovin, Donna J.; Jovin, Thomas M.; Jares‐Erijman, Elizabeth A.

doi:10.1242/jcs.076869

Cited by 31 publications

(29 citation statements)

References 61 publications

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“…S1D and E in the supplemental material), consistent with our previous observations in RBM4-depleted HEK293 cells (18). Moreover, we observed that Rbm4 knockout MEFs and adult muscles had higher levels of exon 11-skipped insulin receptor (IR), i.e., the insulin-insensitive IR-A isoform encoded by IR (19), and exon 8-skipped Pax3, which encodes a dominant negative isoform of the muscle transcription factor Pax3 (20) (Fig. 1D and E).…”

Section: Resultssupporting

confidence: 90%

“…IR-B is the predominant isoform in differentiated pancreatic ␤ cells and shows higher sensitivity to insulin (30). IR-B-activated p38 MAPK signaling is important for both pancreatic development and insulin production from ␤ cells (19). Insulin also activates the phosphatidylinositol-3-kinase-Akt pathway to promote ␤-islet survival and function (33).…”

Section: Discussionmentioning

confidence: 99%

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RBM4 Promotes Pancreas Cell Differentiation and Insulin Expression

Lin

Yan

Hsieh

et al. 2013

Molecular and Cellular Biology

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The RNA-binding protein RNA-binding motif protein 4 (RBM4) modulates alternative splicing of muscle-specific mRNA isoforms during muscle cell differentiation. To better understand the physiological function of RBM4, we exploited a gene knockout strategy in the present study. Mice with targeted disruption of one of the two Rbm4 genes exhibited hyperglycemia coincident with reduced levels of serum insulin and reduced size of pancreatic islets. The embryonic pancreases of Rbm4-deficient mice showed reduced expression or aberrant splicing of many transcripts encoding factors required for pancreas cell differentiation and function. Using pancreatic acinar AR42J cells, we demonstrated that RBM4 promoted insulin gene expression by altering the isoform balance of the transcription factors Isl1 and Pax4 via alternative splicing control. RBM4 overexpression was sufficient to convert AR42J cells into insulin-producing cells. Moreover, RBM4 may mediate glucose-induced insulin expression and insulin receptor isoform switches. These results suggest that RBM4 may have role in promoting pancreas cell differentiation and endocrine function, essentially via alternative splicing regulation. The proteomic complexity of mammalian genomes is greatly expanded by the selective use of exons via alternative splicing. The spatiotemporal expression of alternatively spliced mRNA isoforms contributes substantially to cell differentiation and fate specification and hence influences organogenesis. Reprogramming of alternative splicing during cell differentiation can be achieved by induction of a tissue-specific splicing regulator or by switched expression of one factor to another one that has different or even antagonistic splicing activities. Alternative splicing also provides a mechanism for responding to metabolic prompts (1, 2). Gaining comprehensive insight into alternative splicing remains an imperative goal in the postgenome era.The RNA-binding motif 4 (RBM4) protein has multiple functions in mRNA metabolism; it primarily modulates alterative splicing of precursor mRNAs and regulates mRNA translation (3). We previously reported that RBM4 represses expression of the splicing factor polypyrimidine tract-binding protein (PTB) via alternative splicing-coupled nonsense-mediated mRNA decay during muscle cell differentiation (4). Moreover, RBM4 also modulates the use of alternative exons of many mRNAs encoding muscle differentiation factors or cytoskeletal proteins. Therefore, we deduced that RBM4 promotes myogenesis through its role in altering the repertoire of mRNA isoforms. To further our understanding of the physiological function of RBM4, we attempted to exploit the gene knockout strategy in mice. Previous splicing factor knockout and transgenic studies have revealed the functional consequences of alternative splicing in mammalian development and physiological processes (5). For example, cardiac tissue-specific disruption of the splicing factor gene Srsf1 resulted in abnormal cardiac phenotypes in mice and, moreover, revealed a group of ...

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Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

RBM4 Promotes Pancreas Cell Differentiation and Insulin Expression

Lin

Yan

Hsieh

et al. 2013

Molecular and Cellular Biology

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“…IR-B is the full length mRNA isoform with exon 11 included. It is highly expressed in liver and is reported to be the major INSR isoform involved in insulin metabolism, while IR-A which lacks exon 11 plays a role in promoting cell proliferation (46–48). Here, the average exon inclusion level of INSR exon 11 was 54% in PC-3E but dropped significantly to 33% in GS689.Li (Figure 3C).…”

Section: Resultsmentioning

confidence: 99%

Transcriptome-wide Landscape of Pre-mRNA Alternative Splicing Associated with Metastatic Colonization

Huang

Park

et al. 2015

Molecular Cancer Research

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Metastatic colonization is an ominous feature of cancer progression. Recent studies have established the importance of pre-mRNA alternative splicing (AS) in cancer biology. However, little is known about the transcriptome-wide landscape of AS associated with metastatic colonization. Both in vitro and in vivo models of metastatic colonization were utilized to study AS regulation associated with cancer metastasis. Transcriptome profiling of prostate cancer cells and derivatives crossing in vitro or in vivo barriers of metastasis revealed splicing factors with significant gene expression changes associated with metastatic colonization. These include splicing factors known to be differentially regulated in epithelial-mesenchymal transition (ESRP1, ESRP2, RBFOX2), a cellular process critical for cancer metastasis, as well as novel findings (NOVA1, MBNL3). Finally, RNA-seq indicated a large network of AS events regulated by multiple splicing factors with altered gene expression or protein activity. These AS events are enriched for pathways important for cell motility and signaling, and affect key regulators of the invasive phenotype such as CD44 and GRHL1.

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“…In murine 32D cells, IR-A induces mitogenic and antiapoptotic signals and nuclear translocation of IRS1 , whereas IR-B induces cell differentiation but not IRS1 nuclear translocation . The endocytosis of both IR isoforms in living cells has recently been evaluated using confocal microscopy (Giudice et al 2011). This study has found a higher rate of endocytosis of IR-A compared with IR-B and has correlated these differences with preferential ERK1/2 response to insulin in cells expressing IR-A and preferential Akt response to insulin in cells expressing IR-B.…”

Section: Functional Characteristics Of Ir-a Versus Ir-bmentioning

confidence: 95%

Insulin receptor and cancer

Belfiore

Malaguarnera²

2011

Endocrine-Related Cancer

245

223

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The widespread epidemic of obesity and type 2 diabetes has raised concern for the impact of these disorders as risk factors for cancer and has renewed the interest for studies regarding the involvement of hyperinsulinemia and insulin receptor (IR) in cancer progression. Overexpression of IR in cancer cells may explain their increased sensitivity to hyperinsulinemia. Moreover, IR isoform A (IR-A) together with autocrine production of its ligand IGF2 is emerging as an important mechanism of normal and cancer stem cell expansion and is a feature of several malignancies. De novo activation of the IR-A/IGF2 autocrine loop also represents a mechanism of resistance to anticancer therapies. Increasing knowledge of the IR role in cancer has important implications for cancer prevention, which should include control of insulin resistance and hyperinsulinemia in the population and meticulous evaluation of new antidiabetic drugs for their metabolic:mitogenic ratio. We are now aware that several anticancer treatments may induce or worsen insulin resistance that may limit therapy efficacy. Future anticancer therapies need to target the IR-A pathway in order to inhibit the tumor promoting effect of IR without impairing the metabolic effect of insulin.

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

Cited by 31 publications

References 61 publications

RBM4 Promotes Pancreas Cell Differentiation and Insulin Expression

RBM4 Promotes Pancreas Cell Differentiation and Insulin Expression

Transcriptome-wide Landscape of Pre-mRNA Alternative Splicing Associated with Metastatic Colonization

Insulin receptor and cancer

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