Abstract
AGAP2 (Arf GAP with GTP-binding protein-like domain, Ankyrin repeat and PH domain 2) isoform 2 is a protein that belongs to the Arf GAP (GTPase activating protein) protein family. These proteins act as GTPase switches for Arfs, which are Ras superfamily members, being therefore involved in signaling regulation. Arf GAP proteins have been shown to participate in several cellular functions including membrane trafficking and actin cytoskeleton remodeling. AGAP2 is a multi-tasking Arf GAP that also presents GTPase activity and is involved in several signaling pathways related with apoptosis, cell survival, migration, and receptor trafficking. The increase of AGAP2 levels is associated with pathologies as cancer and fibrosis. Transforming growth factor beta-1 (TGF-β1) is the most potent pro-fibrotic cytokine identified to date, currently accepted as the principal mediator of the fibrotic response in liver, lung, and kidney. Recent literature has described that the expression of AGAP2 modulates some of the pro-fibrotic effects described for TGF-β1 in the liver. The present review is focused on the interrelated molecular effects between AGAP2 and TGFβ1 expression, presenting AGAP2 as a new player in the signaling of this pro-fibrotic cytokine, thereby contributing to the progression of hepatic fibrosis.
Highlights
Actin cytoskeleton remodeling and membrane trafficking are critical processes for the normal function and survival of the cell
Arfs are activated by guanine nucleotide exchange factors (GEFs) which catalyze the exchange of GDP for GTP and are inactivated by GTPase-activating proteins (GAPs) which catalyze the hydrolysis of GTP to GDP [2,3,4]
The discovery of the Arf GAP AGAP2 less than 20 years ago triggered a substantial amount of work trying to elucidate the pathophysiological roles of this GTPase/GTP-activating protein and its mechanisms of action
Summary
Actin cytoskeleton remodeling and membrane trafficking are critical processes for the normal function and survival of the cell. Membrane trafficking is intricately linked to the cytoskeleton, and allows the cell to sort cargo proteins to the correct subcellular compartment through vesicular transport. Arf (ADP-ribosylation factor) proteins, a subfamily of Ras small GTPases, are key regulators in the control of membrane trafficking and organelle structure and contribute to the remodeling of actin cytoskeleton. Arf proteins regulate the recruitment and activation of phosphatidylinositol kinases to modulate membrane lipid composition [1]. Their capacity to participate in cell signaling events is determined by the ratio of GTP-bound (active state) to GDP-bound (inactive state) forms. AresguotlahteorrAofrfceGllAsPigfnaamlinilgy.mAsemotbheerrsA, ArfGGAAPP2fcaamnilbyemaelsmobreergsu, lAatGeAdPth2rcoaungbheoatlhsoerremgeuclhataendisms sreutappchfrehfroaionttauesistigny[mh1fi6oneo]rt.mtehAArbearGrrcfa1tmAin,oAPeenc2rihvfna5aitalnaesioAnrsadmNicnAtsKtieorsrrfnu6aec/pcashteussasbawtossstcirm[tia1aht6eteAim]os. ,rnAbfirnGpavndAriaoeePtcPei2rnieHnataelsssrdioaanocngimtndiootaeernidrx/naaehcsroitsbsoroifwtcpsaiarifhtofthiiitongeAnihitnyrvaf–[ffiipp1ar7rnoPo]i.tHtteyeiindnfsooriamnnAtaderirnfe1ax,cohtAriiobrpfnirt5sovatheinaiigdnhA–ANrfK6 substrates, in decreasing order of affinity [17]
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