Abstract
Insulin/IGF-1 signaling plays a pivotal role in the regulation of cellular homeostasis through its control of glucose metabolism as well as due to its effects on cell proliferation. Aberrant regulation of insulin signaling has been repeatedly implicated in uncontrolled cell growth and malignant transformations. TBC1D3 is a hominoid specific gene previously identified as an oncogene in breast and prostate cancers. Our efforts to identify the molecular mechanisms of TBC1D3-induced oncogenesis revealed the role of TBC1D3 in insulin/IGF-1 signaling pathway. We document here that TBC1D3 intensifies insulin/IGF-1-induced signal transduction through intricate, yet elegant fine-tuning of signaling mechanisms. We show that TBC1D3 expression substantially delayed ubiquitination and degradation of insulin receptor substrate-1 (IRS-1). This effect is achieved through suppression of serine phosphorylation at S636/639, S307 and S312 of IRS-1, which are key phosphorylation sites required for IRS-1 degradation. Furthermore, we report that the effect of TBC1D3 on IRS-1:S636/639 phosphorylation is mediated through TBC1D3-induced activation of protein phosphatase 2A (PP2A), followed by suppression of T389 phosphorylation on p70 S6 kinase (S6K). TBC1D3 specifically interacts with PP2A regulatory subunit B56γ, indicating that TBC1D3 and PP2A B56γ operate jointly to promote S6K:T389 dephosphorylation. These findings suggest that TBC1D3 plays an unanticipated and potentially unique role in the fine-tuning of insulin/IGF-1 signaling, while providing novel insights into the regulation of tumorigenesis by a hominoid-specific protein.
Highlights
Knowledge of genes that are specific to humans is likely to shed light on our understanding of human physiology and pathology
We demonstrated that TBC1D3 expression has a powerful effect on cell proliferation that is further enhanced by epidermal growth factor (EGF) [6]
To determine whether TBC1D3 modulates signal transduction through the insulin receptor, we examined insulin signaling in HepG2 cells (American Type Culture Collection, Manassas, VA), a well-studied human hepatocellular carcinoma cell line
Summary
Knowledge of genes that are specific to humans is likely to shed light on our understanding of human physiology and pathology. TBC1D3 is a hominoid-specific gene that maps to human chromosome 17 [1]. Like many hominoid-specific genes, TBC1D3 appears to have evolved in the primate lineage by segmental duplication [2]. Recent work indicates that TBC1D3 is a multicopied gene in humans [3,4], with variable copy numbers in different individuals [5]. TBC1D3 is one of the first hominoid-specific genes which have been examined at the protein level [6,7], little is known about its function. Initial studies indicate that TBC1D3 is linked to cell proliferation and signaling by growth factor receptors. TBC1D3 expression enhances Ras activation in growth factor-stimulated and unstimulated cells [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
