The emerging role of the fetal insulin receptor (IR-A) in hormone-refractory breast cancer

Endocrinology ◽  
2021 ◽  
Author(s):  
Tanvi Mathur ◽  
Douglas Yee
Keyword(s):  
Growth Factor ◽  
Insulin Receptor ◽  
Biological Effects ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Predictive Biomarker ◽  
Tyrosine Kinase Receptor ◽  
Cancer Therapies ◽  
Insulin Like Growth Factor ◽  
Hormone Refractory

Abstract The type 1 insulin-like growth factor receptor (IGF-1R) is a transmembrane tyrosine kinase receptor and a mediator of the biologic effects of insulin-like growth factor-I and -II (IGF-I/II). Inhibitors of IGF-1R signaling were tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target; essentially all IGF-1R inhibitors failed to provide an additional benefit compared to standard-of-care therapy. In this review, we will evaluate the role the insulin receptor (IR) plays in mediating IGF signaling and subsequent metabolic and mitogenic effects as one possible reason for these failures. IR is expressed as two isoforms, with the fetal isoform IR-A derived from alternative splicing and loss of exon 11, the adult isoform (IR-B) includes this exon. Cancer frequently re-express fetal proteins and this appears to be the case in cancer with a re-expression of the fetal isoform and an increased IR-A: IR-B ratio. The biological effects of IR isoform signaling are complex and not completely understood although it has been suggested that IR-A could stimulate mitogenic signaling pathways, play a role in cancer cell stemness, and mediated tolerance to cancer therapies. From a clinical perspective, the IR-A overexpression in cancer may explain why targeting IGF-1R alone was not successful. However, given the predominance of IR-A expression in cancer, it may also be possible to develop isoform specific inhibitors and avoid the metabolic consequences of inhibiting IR-B. If such inhibitors could be developed, then IR-A expression could serve as a predictive biomarker and co-targeting IR-A and IGF-1R could provide a novel, more effective therapy method.

scholarly journals Secretion of Annexin II via Activation of Insulin Receptor and Insulin-like Growth Factor Receptor

2002 ◽  
Vol 278 (6) ◽  
pp. 4205-4215 ◽  
Author(s):  
Wei-Qin Zhao ◽  
Gina H. Chen ◽  
Hui Chen ◽  
Alessia Pascale ◽  
Lakshmi Ravindranath ◽  
...  
Keyword(s):  
Growth Factor ◽  
Insulin Receptor ◽  
Growth Factor Receptor ◽  
Annexin Ii ◽  
Insulin Like Growth Factor

scholarly journals Determination of Alkali-Sensing Parts of the Insulin Receptor-Related Receptor Using the Bioinformatic Approach

Acta Naturae ◽  
2015 ◽  
Vol 7 (2) ◽  
pp. 80-86 ◽  
Author(s):  
I. E. Deyev ◽  
N. V. Popova ◽  
A. G. Petrenko
Keyword(s):  
Growth Factor ◽  
Insulin Receptor ◽  
Growth Factor Receptor ◽  
Ph Sensitive ◽  
Effective Concentration ◽  
The Body ◽  
Insulin Like Growth Factor ◽  
Extracellular Region ◽  
Half Maximal Effective Concentration ◽  
Receptor Family

IRR (insulin receptor-related receptor) is a receptor tyrosine kinase belonging to the insulin receptor family, which also includes insulin receptor and IGF-IR receptor. We have previously shown that IRR is activated by extracellular fluid with pH 7.9 and regulates excess alkali excretion in the body. We performed a bioinformatic analysis of the pH-sensitive potential of all three members of the insulin receptor family of various animal species (from frog to man) and their chimeras with swapping of different domains in the extracellular region. An analysis using the AcalPred program showed that insulin receptor family proteins are divided into two classes: one class with the optimal working pH in the acidic medium (virtually all insulin receptor and insulin-like growth factor receptor orthologs, except for the IGF-IR ortholog from Xenopus laevis) and the second class with the optimal working pH in the alkaline medium (all IRR orthologs). The program had predicted that the most noticeable effect on the pH-sensitive property of IRR would be caused by the replacement of the L1 and C domains in its extracellular region, as well as the replacement of the second and third fibronectin repeats. It had also been assumed that replacement of the L2 domain would have the least significant effect on the alkaline sensitivity of IRR. To test the in silico predictions, we obtained three constructs with swapping of the L1C domains, the third L2 domain, and all three domains L1CL2 of IRR with similar domains of the insulin-like growth factor receptor. We found that replacement of the L1C and L1CL2 domains reduces the receptors ability to be activated with alkaline pH, thus increasing the half-maximal effective concentration by about 100%. Replacement of the L2 domain increased the half-maximal effective concentration by 40%. Thus, our results indicate the high predictive potential of the AcalPred algorithm, not only for the pH-sensitive enzymes, but also for pH-sensitive receptors.

Upregulation of the Insulin Receptor and Type I Insulin-Like Growth Factor Receptor Are Early Events in Hepatocarcinogenesis

2011 ◽  
Vol 39 (3) ◽  
pp. 524-543 ◽  
Author(s):  
Eiman Aleem ◽  
Dirk Nehrbass ◽  
Fritz Klimek ◽  
Doris Mayer ◽  
Peter Bannasch
Keyword(s):  
Growth Factor ◽  
Insulin Receptor ◽  
Growth Factor Receptor ◽  
Type I ◽  
Insulin Like Growth Factor

scholarly journals Differential Activation of Insulin Receptor Substrates 1 and 2 by Insulin-Like Growth Factor-Activated Insulin Receptors

2007 ◽  
Vol 27 (10) ◽  
pp. 3569-3577 ◽  
Author(s):  
Adam Denley ◽  
Julie M. Carroll ◽  
Gemma V. Brierley ◽  
Leah Cosgrove ◽  
John Wallace ◽  
...  
Keyword(s):  
Growth Factor ◽  
Insulin Receptor ◽  
Splice Variants ◽  
Biological Effects ◽  
Insulin Receptors ◽  
Insulin Like Growth Factor ◽  
Extracellular Signal ◽  
Igf I ◽  
High Concentrations ◽  
Kinase Pathway

ABSTRACT The insulin-like growth factors (insulin-like growth factor I [IGF-I] and IGF-II) exert important effects on growth, development, and differentiation through the IGF-I receptor (IGF-IR) transmembrane tyrosine kinase. The insulin receptor (IR) is structurally related to the IGF-IR, and at high concentrations, the IGFs can also activate the IR, in spite of their generally low affinity for the latter. Two mechanisms that facilitate cross talk between the IGF ligands and the IR at physiological concentrations have been described. The first of these is the existence of an alternatively spliced IR variant that exhibits high affinity for IGF-II as well as for insulin. A second phenomenon is the ability of hybrid receptors comprised of IGF-IR and IR hemireceptors to bind IGFs, but not insulin. To date, however, direct activation of an IR holoreceptor by IGF-I at physiological levels has not been demonstrated. We have now found that IGF-I can function through both splice variants of the IR, in spite of low affinity, to specifically activate IRS-2 to levels similar to those seen with equivalent concentrations of insulin or IGF-II. The specific activation of IRS-2 by IGF-I through the IR does not result in activation of the extracellular signal-regulated kinase pathway but does induce delayed low-level activation of the phosphatidylinositol 3-kinase pathway and biological effects such as enhanced cell viability and protection from apoptosis. These findings suggest that IGF-I can function directly through the IR and that the observed effects of IGF-I on insulin sensitivity may be the result of direct facilitation of insulin action by IGF-I costimulation of the IR in insulin target tissues.

scholarly journals Type 1 Insulin-Like Growth Factor Receptor/Insulin Receptor Substrate 1 Signaling Confers Pathogenic Activity on Breast Tumor Cells Lacking REST

2015 ◽  
Vol 35 (17) ◽  
pp. 2991-3004 ◽  
Author(s):  
Kassondra Meyer ◽  
Brittany Albaugh ◽  
Barry Schoenike ◽  
Avtar Roopra
Keyword(s):  
Growth Factor ◽  
Insulin Receptor ◽  
Tumor Cells ◽  
Breast Tumor ◽  
Growth Factor Receptor ◽  
Insulin Receptor Substrate ◽  
Insulin Like Growth Factor ◽  
Insulin Receptor Substrate 1 ◽  
Breast Tumor Cells

Loss of repressor element 1 silencing transcription factor (REST) occurs in 20% of breast cancers and correlates with a poor patient prognosis. However, the molecular basis for enhanced malignancy in tumors lacking REST (RESTless) is only partially understood. We used multiplatform array data from the Cancer Genome Atlas to identify consistent changes in key signaling pathways. Of the proteins screened in the reverse-phase protein array, we found that insulin receptor substrate 1 (IRS1) is the most highly upregulated protein in RESTless breast tumors. Analysis of breast tumor cell lines showed that REST directly represses IRS1, and cells lacking REST have increased levels of IRS1 mRNA and protein. We find that the upregulation of IRS1 function is both necessary and sufficient for enhanced signaling and growth in breast cancer cells lacking REST. IRS1 overexpression is sufficient to phenocopy the enhanced activation of the signaling hubs AKT and mitogen-activated protein kinase (MAPK) of MCF7 cells lacking REST. Loss of REST renders MCF7 and MDA-MB-231 breast tumor cells dependent on IRS1 activity for colony formation in soft agar. Inhibition of the type 1 insulin-like growth factor receptor (IGF1R) reduces the enhanced signaling, growth, and migration in breast tumor cells that occur upon REST loss. We show that loss of REST induces a pathogenic program that works through the IGF1R/IRS1 pathway.

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