Paving the Rho in cancer metastasis: Rho GTPases and beyond

Article ID	Journal	Published Year	Pages	File Type
8536891	Pharmacology & Therapeutics	2018	73 Pages	PDF

Abstract

The family of Rho GTPases is an ubiquitously expressed division of GTP-binding proteins involved in the regulation of cytoskeletal dynamics and intracellular signaling. The best characterized members of the Rho family GTPases are RhoA, Rac1 and Cdc42. Abnormalities in Rho GTPase function have major consequences for cancer progression. Rho GTPase activation is driven by cell surface receptors that activate GTP exchange factors (GEFs) and GTPase-activating proteins (GAPs). In this review, we summarize our current knowledge on Rho GTPase function in the regulation of metastasis. We will focus on key discoveries in the regulation of epithelial-mesenchymal-transition (EMT), cell-cell junctions, formation of membrane protrusions, plasticity of cell migration and adaptation to a hypoxic environment. In addition, we will emphasize on crosstalk between Rho GTPase family members and other important oncogenic pathways, such as cyclic AMP-mediated signaling, canonical Wnt/Î²-catenin, Yes-associated protein (YAP) and hypoxia inducible factor 1Î± (Hif1Î±) and provide an overview of the advancements and challenges in developing pharmacological tools to target Rho GTPase and the aforementioned crosstalk in the context of cancer therapeutics.

Keywords

ECM MMP RAC GDI GTP AMP DVL COX-2 WRC PGE2 HMGCR TCF APC SRF pKa ADP GPCR AMT PKC S1P CXCR4 RGS PDZ PAK CK1 GSK-3 LPA HRE GTPases MRTF-A CDC42 GEF PDK1 SDF1 pVHL MLC MLCK HIF1α C-X-C motif chemokine receptor 4 Net1 IQGAP LIMK Neural Wiskott-Aldrich syndrome protein N-WASP Smurf1 PLD1 Lats1/2 mDia MRCK DOCK2 TIAM Von hippel-lindau protein Et1 SRA1 lymphoid enhancer-binding factor 1 Ras homolog gene family MLC kinase myocardin-related transcription factor A WAVE regulatory complex 3-Hydroxy-3-Methylglutaryl-coenzyme A reductase Arp2/3 G-protein coupled receptor GTPase Activating Protein adenosine diphosphate adenosine monophosphate adenomatosis polyposis coli Sphingosine 1 phosphate lysophosphatidic acid Fluorescence resonance energy transfer FRET endothelin 1 YAP disheveled GDP EMT larg Rho Regulator of G-protein signaling myosin light chain Cancer NSCLC Trio cyclooxygenase 2 GAP hypoxia inducible factor 1α Transcription factor stromal cell-derived factor 1 hypoxia response element Guanine exchange factor Vascular endothelial growth factor Vascular Endothelial Growth Factor (VEGF)serum response factor Phospholipase D1 Lef Mat Extracellular matrix Matrix metalloprotease Metastasis guanine nucleotide dissociation inhibitor Wave Tead RAS-related C3 botulinum toxin substrate yes-associated protein cell division control protein 42 homolog 3-phosphoinositide-dependent protein kinase 1 protein kinase A Protein kinase C Prostaglandin E2 non-small cell lung carcinoma casein kinase 1 p21-activated kinase Epithelial-mesenchymal transition glycogen synthase kinase 3 guanine triphosphate guanine diphosphate Rock