RHOB expression controls the activity of serine/threonine protein phosphatase PP2A to modulate mesenchymal phenotype and invasion in non-small cell lung cancers.
Metastatic dissemination is the cause of death in the vast majority of cancers, including lung cancers. In order to metastasize, tumor cells must undergo a well-known series of changes, however the molecular details of how they manage to overcome the barriers at each stage remain incomplete. One critical step is acquiring the ability to migrate through the extracellular matrix. Loss of expression of the RAS-related small GTPase RHOB is a common feature of lung cancer progression, and we recently reported that this induces an epithelial-to-mesenchymal transition (EMT) that is dependent on SLUG overexpression and E-Cadherin inhibition and is characterized by 3-dimensional cell shape reorganization and the increased invasiveness of bronchial cells. RHOB loss was found to induce AKT1 activation, which in turn activates RAC1 through its GEF TRIO. Further investigation of this pathway revealed that RHOB interacts with and positively regulates PP2A, one of the major cellular serine-threonine phosphatases, by recruiting its regulatory subunit B55. Here we discuss the role of this newly discovered RHOB/PP2A/AKT1/RAC1 pathway in relation to mesenchymal migration and invasion in lung cancer.
a Inserm, Center de Recherche en Cancérologie de Toulouse, CRCT UMR-1037 , Toulouse , France.|b Université Paul Sabatier , Toulouse , France.
Olivier
O
Calvayrac
a Inserm, Center de Recherche en Cancérologie de Toulouse, CRCT UMR-1037 , Toulouse , France.|b Université Paul Sabatier , Toulouse , France.|c Institut Claudius Regaud, IUCT-Oncopole, Laboratoire de Biologie Médicale Oncologique , Toulouse , France.
Anne
A
Pradines
a Inserm, Center de Recherche en Cancérologie de Toulouse, CRCT UMR-1037 , Toulouse , France.|b Université Paul Sabatier , Toulouse , France.|c Institut Claudius Regaud, IUCT-Oncopole, Laboratoire de Biologie Médicale Oncologique , Toulouse , France.
Gilles
G
Favre
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008648:Mesoderm / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D020743:rhoB GTP-Binding Protein / Q000378:metabolism*
D054648:Protein Phosphatase 2; D020743:rhoB GTP-Binding Protein
PP2A; RHOB; invasion; lung cancer; mesenchymal
Clin Cancer Res. 2014 Dec 15;20(24):6541-50
25320360
Nat Cell Biol. 2003 Aug;5(8):711-9
12844144
Cancer Res. 2009 Aug 1;69(15):6092-9
19602596
FEBS J. 2016 Mar;283(6):1004-24
26507691
Tumour Biol. 2015 Sep;36(9):6901-8
25851347
Oncotarget. 2016 Mar 29;7(13):16745-59
26934447
Leukemia. 2011 Nov;25(11):1711-7
21660042
Oncogene. 2016 Apr 7;35(14):1760-9
26148238
Eur J Clin Invest. 2016 May;46(5):398-407
26919035
Genes Dev. 2003 Nov 1;17(21):2721-32
14597666
Cancer Res. 2016 Mar 15;76(6):1627-40
26759237
Cancer Discov. 2015 Feb;5(2):198-211
25432929
Mol Cell Biol. 2001 Oct;21(20):6906-12
11564874
Carcinogenesis. 2011 Sep;32(9):1299-304
21665887
Clin Cancer Res. 2012 May 15;18(10):2976-86
22434665
JAMA Oncol. 2015 Jul;1(4):505-27
26181261
Exp Cell Res. 2005 Apr 1;304(2):354-64
15748883
Oncogene. 2015 Dec 3;34(49):5971-82
25746002
Mol Cell. 2005 Dec 9;20(5):801-9
16310392
Oncotarget. 2014 Dec 15;5(23 ):12203-17
25356755
J Cell Biol. 2016 May 9;213(3):385-402
27138256
J Biol Chem. 2000 Jun 16;275(24):17974-8
10770919
Tumour Biol. 2016 Sep;37(9):11691-11700
27444275
Lancet Oncol. 2013 May;14(6):e229-38
23639323
Oncotarget. 2015 Mar 10;6(7):5134-46
25762617
Cancer Lett. 2013 Jul 10;335(1):9-18
23454242
Biochim Biophys Acta. 2009 Jan;1795(1):1-15
18588945
Int J Clin Exp Pathol. 2014 Aug 15;7(9):5846-54
25337226
PLoS One. 2016 Jul 06;11(7):e0157599
27384222
Mol Cell Biol. 2014 Aug;34(16):3144-55
24912678
Dev Dyn. 2004 Jan;229(1):136-9
14699585
Cell. 2008 Oct 31;135(3):510-23
18984162
Exp Cell Res. 2008 Jan 1;314(1):68-81
17803990
J Microsc. 2013 Sep;251(3):242-9
23488932
Lancet Oncol. 2001 Jul;2(7):437-42
11905738
Clin Cancer Res. 2002 Jul;8(7):2225-32
12114424
FEBS J. 2013 Jan;280(2):644-61
22443683
J Biol Chem. 2008 Jan 25;283(4):1882-92
18042541
Nat Rev Mol Cell Biol. 2006 Feb;7(2):131-42
16493418
PLoS One. 2012;7(7):e40378
22911700
Cancer Res. 2013 Jan 1;73(1):50-61
23135917
Oncogene. 2003 Sep 18;22(40):6204-13
13679859
Cancer Res. 2012 Dec 15;72(24):6414-24
23087057
Front Biosci (Landmark Ed). 2009 Jan 01;14 :3035-50
19273255
J Biol Chem. 2005 Dec 30;280(52):43257-63
16278215
Cell Commun Signal. 2015 Jan 29;13:6
25630770
Clin Cancer Res. 2005 Nov 15;11(22):8070-8
16299238
Proteomics. 2007 Jan;7(2):206-14
17163575
Cell. 2009 Oct 30;139(3):468-84
19879837
Clin Cancer Res. 2004 Apr 15;10(8):2742-50
15102679
Int J Cancer. 2007 Feb 1;120(3):543-51
17096327
Cell. 1995 Apr 7;81(1):53-62
7536630