Abstract
The insulin-like growth factors (IGFs; IGF1/IGF2), known for their regulation of cell and organismal growth and development, are evolutionarily conserved ligands with equivalent peptides present in flies ( D. melanogaster), worms ( C. elegans) among others. Two receptor tyrosine kinases, the IGF1 receptor and the insulin receptor mediate the actions of these ligands with a family of IGF binding proteins serving as selective inhibitors of IGF1/2. This treatise reviews recent findings on IGF signaling in cancer biology and central nervous system function. This includes overexpression of IGF1 receptors in enhancing tumorigenesis, acquired resistance and contributions to metastasis in multiple cancer types. There is accumulating evidence that insulin resistance, a hallmark of type 2 diabetes, occurs in the central nervous system, independent of systemic insulin resistance and characterized by reduced insulin and IGF1 receptor signaling, and may contribute to dementias including Alzheimer’s Disease and cognitive impairment. Controversy over the role(s) of IGF signaling in cancer and whether its inhibition would be of benefit, still persist and extend to IGF1’s role in longevity and central nervous system function.
Highlights
insulin-like growth factors (IGFs)-1 and members of the IGF family In mammals, the insulin-like growth factor (IGF) family comprises three ligands—IGF-1, IGF-2, and insulin—and three receptors—the IGF-1 receptor (IGF1R), insulin receptor (IR), and IGF-2 receptor (IGF2R)
Qiu and co-workers[36] reported that both primary and acquired resistance of breast cancer cell lines to the anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody (mAb) trastuzumab are both increased by Cullin[7] (CUL7), a scaffold protein for the CUL7 E3 ubiquitin ligase that is overexpressed in the trastuzumab-resistant cells
CUL7 overexpression favors signaling through Tyr-phosphorylated insulin receptor substrate 1 (IRS1), which is reinforced by CUL7 degradation of IGFBP3, in turn raising IGF-1 levels and IGF1R signaling, which enhances resistance to trastuzumab[36]
Summary
F1000 Faculty Reviews are written by members of the prestigious F1000 Faculty. They are commissioned and are peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Any comments on the article can be found at the end of the article
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