ADP-ribosylation factor 6 regulates glioma cell invasion through the IQ-domain GTPase-activating protein 1-Rac1-mediated pathway.
A common pathobiological feature of malignant gliomas is the insidious infiltration of single tumor cells into the brain parenchyma, rendering these deadly tumors virtually incurable with available therapies. In this study, we report that ADP-ribosylation factor 6 (ARF6), a Ras superfamily small GTPase, is abundantly expressed in invasive human glioma cells. Cellular depletion of ARF6 by small interfering RNA decreased Rac1 activation, impaired HGF-stimulated and serum-stimulated glioma cell migration in vitro, and markedly decreased the invasive capacity of invasive glioma in the brain. Furthermore, ectopic expression of ARF6 in glioma cells promoted cell migration via the activation of Rac1. Upon stimulation of glioma cells with HGF, we show that IQ-domain GTPase-activating protein 1 (IQGAP1) is recruited and overlaps with ARF6 at the leading edge of migrating cells. However, cellular depletion of ARF6 abrogated this recruitment of IQGAP1 and attenuated the formation of surface protrusions. ARF6 forms complexes with Rac1 and IQGAP1 in glioma cells upon HGF stimulation, and knockdown of IQGAP1 significantly inhibits ARF6-induced Rac1 activation and cell migration. Taken together, these data suggest that ARF6-mediated Rac1 activation is essential for glioma cell invasion via a signaling pathway that requires IQGAP1.
Hu
Bo
B
Departments of Medicine and Pathology, Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. hub@upmc.edu
Shi
Binhai
B
Jarzynka
Michael J
MJ
Yiin
Jia-Jean
JJ
D'Souza-Schorey
Crislyn
C
Cheng
Shi-Yuan
SY
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000502:physiology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*
D000089982:ADP-Ribosylation Factor 6; C101203:IQ motif containing GTPase activating protein 1; C107953:RAC1 protein, human; D034741:RNA, Small Interfering; D020703:ras GTPase-Activating Proteins; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse; D020830:rac1 GTP-Binding Protein