Disease relevance of ARF1

• In infected HeLa cells, an ARF1-enhanced green fluorescent protein fusion redistributes from Golgi stacks to the perinuclear region, where poliovirus RNA replication occurs [1].
• PLD activity in both intact cells and the ARF-restored response in cytosol-depleted cells is inhibited by pertussis toxin, indicating a requirement for Gi2/Gi3 protein [2].
• Effect of Rho and ADP-ribosylation factor GTPases on phospholipase D activity in intact human adenocarcinoma A549 cells [3].
• CONCLUSIONS: This study demonstrates: (a) a high frequency and specificity of INK4a/ARF methylation in malignant biliary disease compared with mere cholangitis; and (b) the capability to detect these alterations reliably in endoscopically obtained bile [4].
• Arfaptin 1 inhibits ADP-ribosylation factor-dependent matrix metalloproteinase-9 secretion induced by phorbol ester in HT 1080 fibrosarcoma cells [5].
• These results uncover a novel molecular mechanism by which ARF1 regulates breast cancer cell growth and invasion during cancer progression [6].

High impact information on ARF1

• In vivo, ARF6, but not ARF1 or ARF5, spatially coincides with PI(4)P5Kalpha [7].
• ADP-ribosylation factor, a small GTP-dependent regulatory protein, stimulates phospholipase D activity [8].
• The factor was purified to homogeneity from bovine brain cytosol and identified as a member of the ADP-Ribosylation Factor (ARF) subfamily of small G proteins [8].
• The assembly of coated buds on the membranes requires coatomer, ARF, and GTP [9].
• Budding of COP-coated vesicles (the likely carriers of newly synthesized proteins from the endoplasmic reticulum through the Golgi stack) from Golgi cisternae requires ADP-ribosylation factor (ARF), coatomer proteins from the cytosol, GTP, and fatty acyl-coenzyme A (CoA) [9].

Chemical compound and disease context of ARF1

• To identify the signaling pathway to ARF and Rho activation by fMLP, we used pertussis toxin and wortmannin to examine the requirement for heterotrimeric G proteins of the Gi family and for phosphoinositide 3-kinase, respectively [2].
• The accumulation of ARFs on membranes correlates with active replication of poliovirus RNA in vitro, whereas ARF translocation to membranes does not occur in the presence of BFA [1].

Biological context of ARF1

• Two other human ARF cDNA sequences, designated human ARF1 and ARF3, have been reported previously and are 96% identical in amino acid sequence [10].
• Exocytosis from cytosol-depleted permeabilised chromaffin cells was not increased by adding recombinant nonmyristoylated or myristoylated ARF1, and exocytosis from both cell types was resistant to brefeldin A (BFA) [11].
• Since ARF1-regulated PLD activity requires phosphatidylinositol 4,5-bisphosphate (PIP2), the distributions of inositol lipids and the kinases responsible for lipid phosphorylation were examined [12].
• Moreover, ARF1-regulated PLD is part of the signal-transduction pathway that can lead to secretion [13].
• ARF is an essential gene in the yeast, Saccharomyces cerevisiae, and is encoded by two genes [10].

Anatomical context of ARF1

• Treatment with brefeldin A or overexpression of dominant-negative ADP ribosylation factor 1 (ARF1) caused dissociation of GGAs from membranes [14].
• Second, adding constitutively active Q71L ARF1 to the cytosol has the same effect as adding GTPgammaS [15].
• Two lines of evidence indicate that the GTPgammaS-induced targeting of AP-2 to endosomes is mediated by ADP-ribosylation factor-1 (ARF1) [15].
• Ceramide inhibition of phospholipase D and its relationship to RhoA and ARF1 translocation in GTP gamma S-stimulated polymorphonuclear leukocytes [16].
• ARF1 and ARF6 are both expressed in HL60 cells and can be depleted from the cells by permeabilization [17].

Associations of ARF1 with chemical compounds

• Some aptamers inhibit guanine-nucleotide exchange on ARF1, thereby preventing ARF activation in vitro [18].
• Cytohesin-1 also increased ARF1 binding to a Golgi fraction, but its effect was not inhibited by brefeldin A (BFA), a drug that reversibly inhibits Golgi function [19].
• In comparison, ARF1 activates PLD, producing PA, which is a known activator of phosphatidylinositol-4-phosphate 5 kinase, the enzyme responsible for PIP2 synthesis [20].
• PI(4,5)P(2) synthesis stimulated by ARF1 was not blocked by 0.5% butanol but could be blocked by 1.5% butanol [17].
• C2- and C8-ceramides prevented the GTPgammaS-induced translocation of ARF1 and RhoA from the cytosol to the membrane fraction [21].

Physical interactions of ARF1

• Arfaptin effects on guanine nucleotide binding by ARFs were minimal whether or not a purified ARF guanine nucleotide-exchange protein was present [22].
• Using in vitro binding assay, we show that ARF1 and RalA directly interact with different sites of PLD1 [23].
• Cytohesin-1 enhanced binding of 35S-labeled guanosine 5'-[gamma-thio]triphosphate [35S]GTP[gammaS] or [3H]GDP to ARF purified from bovine brain (i.e., it appeared to function as an ARF-GEP) [19].
• Here, we identify ARHGAP10--a novel Rho GTPase-activating protein (Rho-GAP) that is recruited to Golgi membranes through binding to GTP-ARF1 [24].
• In contrast, mu4 binds equally well to the GTP- and GDP-bound forms of ARF1 and is less dependent on switch I and switch II residues [25].

Regulatory relationships of ARF1

• Furthermore, ARF-1 stimulated endogenous PLD activity in Golgi membranes approximately threefold and this activation correlated with its enhancement of vesicle budding [26].
• Cloning and initial characterization of a human phospholipase D2 (hPLD2). ADP-ribosylation factor regulates hPLD2 [27].
• RESULTS: Wild type ARNO transiently transfected in HIRcB cells was translocated to the plasma membrane in an insulin-dependent manner and promoted the translocation of ARF to the membranes [28].
• Budding of transport vesicles in the Golgi apparatus requires the recruitment of coat proteins and is regulated by ADP ribosylation factor (ARF) 1 [29].
• Previously, it has been shown that the RCC1-like domain 1 (RLD1) of HERC1 stimulates guanine nucleotide dissociation on ARF1 and Rab proteins [30].

Other interactions of ARF1

• We show that all three proteins act as ARF1 GEF in vitro, whereas they have no effect on ARF6, an ARF protein implicated in the early endocytic pathway [29].
• Arfaptin 1 inhibited activation of both enzymes in a concentration-dependent manner and was without effect in the absence of ARF [22].
• Cardiac phospholipase D2 localizes to sarcolemmal membranes and is inhibited by alpha-actinin in an ADP-ribosylation factor-reversible manner [31].
• Both hARF1 and hARF4 encode GTP-binding proteins with predicted molecular masses of 20,000-21,000 Da [10].
• Arfaptin 2 was also ubiquitously expressed and bound to the GTP-, but not GDP-liganded form of class I ARFs, especially ARF1 [32].

Analytical, diagnostic and therapeutic context of ARF1

• These findings were corroborated by experiments investigating co-immunoprecipitation of the wild type (WT) and N376D mutant of the 5-HT(2A) receptor with ARF1 or 6 or dominant negative ARF1/6 constructs co-expressed in COS7 cells [33].
• Northern blot analysis revealed the expression of at least three different ARF messages in human placenta and adrenal carcinoma cells [10].
• This finding suggests that ARF1 is not a regulator of specific coat proteins, but rather is a ubiquitous molecular switch that acts as a transducer of diverse signals influencing coat assembly [34].
• Membrane contents of ARF were assessed by Western blotting with the anti-ARF monoclonal antibody 1D9 followed by densitometric evaluation [35].
• Promoter methylation of INK4a/ARF as detected in bile-significance for the differential diagnosis in biliary disease [4].

References