The sirtuins promote Dishevelled-1 scaffolding of TIAM1, Rac activation and cell migration

Oncogene
M SaxenaK Pruitt

Abstract

Rac1-GTPases serve as intermediary cellular switches, which conduct transient and constitutive signals from upstream cues, including those from Ras oncoproteins. Although the sirtuin1 (SIRT1) deacetylase is overexpressed in several human cancers and has recently been linked to cancer cell motility as a context-dependent regulator of multiple pathways, its role in Rac1 activation has not been reported. Similarly, SIRT2 has been demonstrated to be upregulated in some cancers; however, studies have also reported its role in tumor suppression. Here, we demonstrate that SIRT1 and SIRT2 positively regulate the levels of Rac1-GTP and the activity of T-cell lymphoma invasion and metastasis 1 (TIAM1), a Rac guanine nucleotide exchange factor (GEF). Transient inhibition of SIRT1 and SIRT2 resulted in increased acetylation of TIAM1, whereas chronic SIRT2 knockdown resulted in enhanced acetylation of TIAM1. SIRT1 regulates Dishevelled (DVL) protein levels in cancer cells, and DVL along with TIAM1 are known to augment Rac activation; however, SIRT1 or 2 has not been previously linked with TIAM1. We found that diminished sirtuin activity led to the disruption of the DVL1-TIAM1 interaction. We hence propose a model for Rac activation where SI...Continue Reading

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Citations

Jan 9, 2015·International Journal of Molecular Sciences·Glenn E SimmonsKevin Pruitt
Jan 30, 2016·Breast Cancer Research : BCR·Kun XuRachel J Buchsbaum
Jul 30, 2016·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Boopathi SubramaniyanGaneshan Mathan
Apr 11, 2018·Journal of Cardiothoracic Surgery·Ming-Chun MaShau-Hsuan Li
Dec 2, 2015·Genes & Cancer·Somnath PandeyKevin Pruitt
Oct 28, 2017·Scientific Reports·Lei QiangYu-Ying He
Jul 2, 2020·International Journal of Hepatology·Meseret Derbew MollaBirhanu Ayelign
Aug 5, 2017·Mediators of Inflammation·Luigi Mario CastelloAnnalisa Chiocchetti
Nov 18, 2020·Biochemical Society Transactions·Joe MaltasAngeliki Malliri
Aug 22, 2014·Molecular Cancer Research : MCR·Lijia ZhuYan Dai
Jun 21, 2018·Molecular Cancer Research : MCR·Deborah MolehinKevin Pruitt
Nov 1, 2020·International Journal of Molecular Sciences·Monica Sharma, Kevin Pruitt
Dec 18, 2020·Frontiers in Cell and Developmental Biology·Fahmida RashaKevin Pruitt
Apr 17, 2021·EMBO Reports·Isabel Castro-PiedrasKevin Pruitt
Mar 26, 2015·Chemical Reviews·Hui Jing, Hening Lin
Sep 29, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Arushi TanejaNagalingam Ravi Sundaresan

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Methods Mentioned

BETA
GTPases
GTPase
acetylation
pull down
immunoprecipitation
co-immunoprecipitation assay
immunoprecipitations
pull-down

Software Mentioned

AxioVision
Image J

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