The small GTPase ARF6 regulates protein trafficking to control cellular function during development and in disease

Grossmann, Allie H.; Zhao, Helong; Jenkins, Noah; Zhu, Weiquan; Richards, Jackson R.; Yoo, Jae Hyuk; Winter, Jacob M.; Rich, Bianca E.; Mleynek, Tara; Li, Dean Y.; Odelberg, Shannon J.

doi:10.1080/21541248.2016.1259710

Cited by 31 publications

(42 citation statements)

References 83 publications

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“…40-44), as well as a variety of endothelial and epithelial cells (reviewed in ref. 6). These data support a biologic role for activated ARF6 specifically in tumor cell function.…”

Section: Arf6 Is Aberrantly Activated In Melanoma Patient Samplesmentioning

confidence: 99%

“…A hallmark of melanoma is early, aggressive spread of disease when primary tumors are as thin as 1 mm (1). The small GTPase adenosine diphosphate (ADP)-ribosylation factor 6 (ARF6) controls invasion of cutaneous melanoma (2)(3)(4)(5) and other cancers (6). In its active, GTP-bound state, ARF6 promotes invasion whereas inactive, GDP-bound ARF6 reduces invasion (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

“…In uveal melanoma, ARF6 is activated by mutant GNAQ to control tumor growth (7). Beyond melanoma, ARF6 is activated by and coordinates signaling from a variety of signals including EGFR (6), HER2/ERBB2 (8), c-MET (9), VEGFR2 (6), Frizzled (2,10), inflammatory receptors (6), and G-Protein-coupled receptors (6). In addition, ARF6 has a critical role in the functional output of mutant p53 (11) and RAS (12).…”

Section: Introductionmentioning

confidence: 99%

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The Small GTPase ARF6 Activates PI3K in Melanoma to Induce a Prometastatic State

et al. 2019

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Inv ad op od iu m Melanoma has an unusual capacity to spread in early-stage disease, prompting aggressive clinical intervention in very thin primary tumors. Despite these proactive efforts, patients with low-risk, low-stage disease can still develop metastasis, indicating the presence of permissive cues for distant spread. Here, we show that constitutive activation of the small GTPase ARF6 (ARF6 Q67L) is sufficient to accelerate metastasis in mice with BRAF V600E /Cdkn2a NULL melanoma at a similar incidence and severity to Pten loss, a major driver of PI3K activation and melanoma metastasis. ARF6 Q67L promoted spontaneous metastasis from significantly smaller primary tumors than PTEN NULL , implying an enhanced ability of ARF6-GTP to drive distant spread. ARF6 activation increased lung colonization from circulating melanoma cells, suggesting that the prometastatic function of ARF6 extends to late steps in metastasis. Unexpectedly, ARF6 Q67L tumors showed upregulation of Pik3r1 expression, which encodes the p85 regulatory subunit of PI3K. Tumor cells expressing ARF6 Q67L displayed increased PI3K protein levels and activity, enhanced PI3K distribution to cellular protrusions, and increased AKT activation in invadopodia. ARF6 is necessary and sufficient for activation of both PI3K and AKT, and PI3K and AKT are necessary for ARF6-mediated invasion. We provide evidence for aberrant ARF6 activation in human melanoma samples, which is associated with reduced survival. Our work reveals a previously unknown ARF6-PI3K-AKT proinvasive pathway, it demonstrates a critical role for ARF6 in multiple steps of the metastatic cascade, and it illuminates how melanoma cells can acquire an early metastatic phenotype in patients. Significance: These findings reveal a prometastatic role for ARF6 independent of tumor growth, which may help explain how melanoma spreads distantly from thin, early-stage primary tumors.

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“…40-44), as well as a variety of endothelial and epithelial cells (reviewed in ref. 6). These data support a biologic role for activated ARF6 specifically in tumor cell function.…”

Section: Arf6 Is Aberrantly Activated In Melanoma Patient Samplesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Small GTPase ARF6 Activates PI3K in Melanoma to Induce a Prometastatic State

et al. 2019

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“…Arf6 is a member of the Arf family which exhibits pleiotropic biological functions ( 7 , 30 – 33 ). Arf6 has been reported to be upregulated in multiple types of tumor, and has been demonstrated to be involved in a number of biological processes, including cancer cell growth, EMT, cell adhesion, migration, invasion, angiogenesis, malignant transformation and resistance to chemotherapy ( 18 , 24 , 34 – 36 ).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Arf6 increases drug sensitivity and inhibits proliferation, migration and invasion in gastric cancer SGC‑7901 cells

Qiu

Tao

Wei³

et al. 2017

Oncol Lett

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ADP-ribosylation factor 6 (Arf6), a member of the ADP-ribosylation factor family, is overexpressed in different types of cancer cell and promotes invasion, metastasis and drug resistance. However, the potential functions of Arf6 in gastric cancer (GC), and the molecular mechanism underlying these functions, remain to be fully elucidated. In the present study, the results demonstrated that in vitro knockdown of Arf6 decreased proliferation, colony formation, migration and invasion in SGC-7901 cells. Arf6 knockdown also markedly decreased the activity of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Furthermore, knockdown of Arf6 was associated with elevated chemosensitivity of SGC-7901 cells to 5-fluorouracil through inactivation of the ERK1/2 signaling pathway. Taken together, these results suggest that Arf6 is involved in regulating proliferation, migration, invasion and drug resistance in GC, and may be a potential therapeutic target for the treatment of GC.

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“…Arf6, the least conserved member of the Arf family of GTPases, belongs to the Ras GTPase superfamily and localizes to the plasma membrane (PM) and endosomal compartments (D'Souza-Schorey and Chavrier, 2006). Arf6 is activated downstream from Met (Palacios and D'Souza-Schorey, 2003;Miura et al, 2017) and regulates endocytic membrane trafficking (Gillingham and Munro, 2007;Grossmann et al, 2019), including the Met RTK (Parachoniak et al, 2011). Arf6 also regulates the remodeling of actin cytoskeleton and FA dynamics to control cell motility (D'Souza-Schorey et al, 1997;Radhakrishna and Donaldson, 1997;Matsumoto et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Arf6 regulates RhoB subcellular localization to control cancer cell invasion

Zaoui

Rajadurai

Duhamel

et al. 2019

Journal of Cell Biology

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The ADP-ribosylation factor 6 (Arf6) is a small GTPase that regulates endocytic recycling processes in concert with various effectors. Arf6 controls cytoskeletal organization and membrane trafficking; however, the detailed mechanisms of regulation remain poorly understood. Here, we report that Arf6 forms a complex with RhoB. The interaction between RhoB and Arf6 is mediated by the GCI (glycine, cysteine, and isoleucine) residues (188–190) of RhoB. Specific targeting of Arf6 to plasma membrane or mitochondrial membranes promotes recruitment and colocalization of RhoB to these membrane microdomains. Arf6 depletion promotes the loss of RhoB from endosomal membranes and leads to RhoB degradation through an endolysosomal pathway. This results in defective actin and focal adhesion dynamics and increased 3D cell migration upon activation of the Met receptor tyrosine kinase. Our findings identify a novel regulatory mechanism for RhoB localization and stability by Arf6 and establish the strict requirement of Arf6 for RhoB-specific subcellular targeting to endosomes and biological functions.

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The small GTPase ARF6 regulates protein trafficking to control cellular function during development and in disease

Cited by 31 publications

References 83 publications

The Small GTPase ARF6 Activates PI3K in Melanoma to Induce a Prometastatic State

The Small GTPase ARF6 Activates PI3K in Melanoma to Induce a Prometastatic State

Knockdown of Arf6 increases drug sensitivity and inhibits proliferation, migration and invasion in gastric cancer SGC‑7901 cells

Arf6 regulates RhoB subcellular localization to control cancer cell invasion

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