Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis.

Cen Zhang,Xuetian Yue,Zhaohui Feng,Juan Liu,Xiaolong Wang,Yuhan Zhao,Shaohua Li,Yu Zhu,Felix Blanco,Wenwei Hu,Gyan Bhanot,Hao Wu,Bruce G Haffty

doi:10.7554/elife.10727

Abstract

Glutaminase (GLS) isoenzymes GLS1 and GLS2 are key enzymes for glutamine metabolism. Interestingly, GLS1 and GLS2 display contrasting functions in tumorigenesis with elusive mechanism; GLS1 promotes tumorigenesis, whereas GLS2 exhibits a tumor-suppressive function. In this study, we found that GLS2 but not GLS1 binds to small GTPase Rac1 and inhibits its interaction with Rac1 activators guanine-nucleotide exchange factors, which in turn inhibits Rac1 to suppress cancer metastasis. This function of GLS2 is independent of GLS2 glutaminase activity. Furthermore, decreased GLS2 expression is associated with enhanced metastasis in human cancer. As a p53 target, GLS2 mediates p53's function in metastasis suppression through inhibiting Rac1. In summary, our results reveal that GLS2 is a novel negative regulator of Rac1, and uncover a novel function and mechanism whereby GLS2 suppresses metastasis. Our results also elucidate a novel mechanism that contributes to the contrasting functions of GLS1 and GLS2 in tumorigenesis.

Highlights

Metabolic changes are a hallmark of cancer cells (Berkers et al, 2013; Cairns et al, 2011; Ward and Thompson, 2012)
Knockdown of endogenous GLS2 greatly promoted the interaction of endogenous Tiam1 and VAV-1 with endogenous Rac1 in Huh-1 and HepG2 cells (Figure 3H). These results suggest that GLS2 inhibits the Rac1 activation by interacting with Rac1-guanosine 50-diphosphate (GDP) to block its interaction with Rac1 guanine-nucleotide exchange factors (GEFs), such as Tiam1 and VAV1
GLS2 bound to Rac1-GDP through its Switch I & II regions, which is the binding domain for Rac1 GEFs Tiam1 and VAV1

Summary

Introduction

Metabolic changes are a hallmark of cancer cells (Berkers et al, 2013; Cairns et al, 2011; Ward and Thompson, 2012). Recent studies have shown that increased glutamine metabolism plays a critical role in supporting the high proliferation and survival of cancer cells by providing pools of the TCA cycle intermediates, as well as the biosynthesis of proteins, lipids, and nucleotides (Berkers et al, 2013; Cairns et al, 2011; DeBerardinis et al, 2007; Hensley et al, 2013; Ward and Thompson, 2012). Two genes encode glutaminases in human cells: GLS1

Methods

Results

Conclusion