Differences in the ratio of RNA encoding two isoforms of the insulin receptor between control and NIDDM patients. The RNA variant without Exon 11 predominates in both groups

The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR-A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy.

Download Full-text

Evidence for tissue-specific alternative splicing of the ovine insulin receptor gene

Proceedings of the British Society of Animal Science ◽

10.1017/s1752756200597488 ◽

1998 ◽

Vol 1998 ◽

pp. 96-96

Author(s):

P.D. McGrattan ◽

A.R.G. Wylie ◽

A.J. Bjourson

Keyword(s):

Alternative Splicing ◽

Insulin Receptor ◽

Receptor Gene ◽

Protein Isoforms ◽

Common Mechanism ◽

Mrna Transcript ◽

Insulin Receptor Gene ◽

Tissue Specific ◽

Specific Regulation ◽

Exon 11

Alternative splicing of a discrete 36 base pair segment (exon 11) of the human and rat insulin receptor leads to the formation of high and low affinity isoforms differing as much as 3-fold in affinity for insulin. Alternative splicing is a common mechanism for generating protein isoforms and is often regulated in a tissue-specific fashion (Seino & Bell, 1989; Mosthaf et al., 1990). In humans, the lower affinity (B-isoform) mRNA transcript is predominantly expressed in tissues that are important for modulating glucose homeostasis such as the liver and muscle whereas the higher affinity (A-isoform) mRNA transcript is predominantly expressed in haematopoietic tissues such as spleen. Alternative splicing of the region of the ovine insulin receptor gene encoding exon 11 has recently been demonstrated (McGrattan et al., unpublished). The objective of the present study was to establish whether tissue-specific regulation of alternative splicing of the insulin receptor gene occurs in the ruminant animal.

Download Full-text

Evidence for tissue-specific alternative splicing of the ovine insulin receptor gene

Proceedings of the British Society of Animal Science ◽

10.1017/s0308229600033092 ◽

1998 ◽

Vol 1998 ◽

pp. 96-96

Author(s):

P.D. McGrattan ◽

A.R.G. Wylie ◽

A.J. Bjourson

Keyword(s):

Alternative Splicing ◽

Insulin Receptor ◽

Receptor Gene ◽

Protein Isoforms ◽

Common Mechanism ◽

Mrna Transcript ◽

Insulin Receptor Gene ◽

Tissue Specific ◽

Specific Regulation ◽

Exon 11

Alternative splicing of a discrete 36 base pair segment (exon 11) of the human and rat insulin receptor leads to the formation of high and low affinity isoforms differing as much as 3-fold in affinity for insulin. Alternative splicing is a common mechanism for generating protein isoforms and is often regulated in a tissue-specific fashion (Seino & Bell, 1989; Mosthaf et al., 1990). In humans, the lower affinity (B-isoform) mRNA transcript is predominantly expressed in tissues that are important for modulating glucose homeostasis such as the liver and muscle whereas the higher affinity (A-isoform) mRNA transcript is predominantly expressed in haematopoietic tissues such as spleen. Alternative splicing of the region of the ovine insulin receptor gene encoding exon 11 has recently been demonstrated (McGrattan et al., unpublished). The objective of the present study was to establish whether tissue-specific regulation of alternative splicing of the insulin receptor gene occurs in the ruminant animal.

Download Full-text

Silencing of the Insulin Receptor Isoform A Favors Formation of Type 1 Insulin-Like Growth Factor Receptor (IGF-IR) Homodimers and Enhances Ligand-Induced IGF-IR Activation and Viability of Human Colon Carcinoma Cells

Endocrinology ◽

10.1210/en.2009-1006 ◽

2010 ◽

Vol 151 (4) ◽

pp. 1418-1427 ◽

Cited By ~ 17

Author(s):

G. V. Brierley ◽

S. L. Macaulay ◽

B. E. Forbes ◽

J. C. Wallace ◽

L. J. Cosgrove ◽

...

Keyword(s):

Insulin Receptor ◽

Growth Factor Receptor ◽

Colon Adenocarcinoma ◽

Human Colon ◽

Clonogenic Survival ◽

Colon Carcinoma Cells ◽

Adenocarcinoma Cells ◽

Exon 11 ◽

Interfering Rna

Insulin receptor (IR) overexpression is common in cancers, with expression of the A isoform (IR-A, exon 11−) predominating over the B isoform. The IR-A signals a proliferative, antiapoptotic response to IGF-II, which itself can be secreted by tumors to establish an autocrine proliferative loop. Therefore, IGF-II signaling via the IR-A could mediate resistance to type 1 IGF receptor (IGF-IR) inhibitory drugs that are currently in development. This study addressed the role of the IR-A, using a small interfering RNA-based approach in SW480 human colon adenocarcinoma cells that coexpress the IGF-IR. Clonogenic survival was inhibited by depletion of the IGF-IR but not the IR-A, and dual receptor depletion had no greater effect than IGF-IR knockdown alone, suggesting that the IR-A could not compensate for IGF-IR loss. IGF-IR knockdown also resulted in a decrease in viability, whereas IR-A depletion resulted in increased viability. Consistent with this, upon IR-A depletion, we found a concomitant enhancement of IGF-IR activation by IGF-I and IGF-II, reduced formation of IGF-IR:IR-A hybrid receptors and increased IGF-IR homodimer formation. Together, these results suggest that IGF bioactivity is mediated more effectively by the IGF-IR than by the IR-A or receptor hybrids and that signaling via the IGF-IR is dominant to the IR-A in colon cancer cells that express both receptors.

Download Full-text

Tissue-specific differences in insulin receptor m-RNA isoform ratio in two dairy cow breeds

Proceedings of the British Society of Animal Science ◽

10.1017/s1752756200011613 ◽

2003 ◽

Vol 2003 ◽

pp. 2-2

Author(s):

A.R.G. Wylie ◽

D.J. Devlin

Keyword(s):

Alternative Splicing ◽

Insulin Receptor ◽

Cell Lines ◽

Dairy Cow ◽

Base Pair ◽

Preliminary Investigation ◽

Practical Significance ◽

Fat Depots ◽

Lactational Performance ◽

Exon 11

The insulin receptor (IR) is one participant in the partitioning of absorbed nutrients to, and between, the insulin-responsive tissues of animals. We previously reported the alternative splicing of a 36 base pair exon 11 segment of the sheep IR gene and found differences in the ratio of the resultant 11 m-RNA and 11+m-RNA isoforms between muscle and fat depots in crossbred, but not purebred, Texel lambs (McGrattan et al., 1998). Because the IR isoforms, when expressed in cultured cell lines, differ in affinity for insulin by two fold or more (McClain, 1991), variations in the ratio of IR isoform expression may have practical significance for the partitioning of nutrients between tissues and thus for differences in lean and fat gain between the purebred and crossbred lambs. Similarly, variation in IR m-RNA isoform ratios amongst the adipose depots in different breeds of dairy cow could have practical significance for differences in the ability of the breeds to store and mobilise energy and thus for differences in lactational performance between dairy breeds. This study is a preliminary investigation of this hypothesis.

Download Full-text

Differential gene expression of insulin receptor isoforms A and B and insulin receptor substrates 1, 2 and 3 in rat tissues: modulation by aging and differentiation in rat adipose tissue

Journal of Molecular Endocrinology ◽

10.1677/jme.1.01635 ◽

2005 ◽

Vol 34 (1) ◽

pp. 153-161 ◽

Cited By ~ 39

Author(s):

R Serrano ◽

M Villar ◽

C Martínez ◽

J M Carrascosa ◽

N Gallardo ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Receptor ◽

Differential Gene Expression ◽

Target Tissue ◽

Insulin Receptor Isoforms ◽

Alternatively Spliced ◽

Differential Gene ◽

Exon 11

The insulin receptor (IR) occurs as two alternatively spliced isoforms, IR-A (exon 11−) and IR-B (exon 11+), which exhibit functional differences and are expressed in a tissue-specific manner. The IR substrate (IRS) proteins 1, 2 and 3 also differ in function and tissue distribution. Here we show the differential gene expression of IRs and IRSs in several rat target tissues of insulin action. IR-B is significantly higher than IR-A in epididymal white adipose tissue and adipogenesis induces a shift in the alternatively spliced species of IR from the A to the B isoform. Moreover, since aging in the rat is associated with the development of insulin resistance we looked for alterations of expression of these proteins in adipocytes from old rats. Our results reveal that there is a specific decrease in the expression of the IR-B isoform, as well as both mRNA and protein levels of IR, IRS-1 and IRS-3 being significantly decreased, in epididymal adipose tissue from old compared with adult rats. It is concluded that the down-regulation of early components of the insulin transduction pathway in a primary insulin target tissue could be related to the insulin resistance of aging.

Download Full-text