Regulation of HGF-induced hepatocyte proliferation by the small GTPase Arf6 through the PIP2-producing enzyme PIP5K1A

Tsai, Meng-Tsz; Katagiri, Naohiro; Ohbayashi, Norihiko; Iwasaki, Kenichi; Ohkohchi, Nobuhiro; Ding, Shih‐Torng; Kanaho, Yasunori; Funakoshi, Yuji

doi:10.1038/s41598-017-09633-z

Cited by 15 publications

(14 citation statements)

References 30 publications

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“…A role for ARF6 in the PIP2 synthetic pathway was originally described by Honda and colleagues (62), who showed that synthesis of PIP2 by phosphatidylinositol 4-phosphate 5-kinasea (PI4P5Ka) is stimulated by ARF proteins and phosphatidic acid. A more recent report shows that ARF6 controls PI4P5Ka-mediated PIP2 generation and AKT activation in benign hepatocytes (44). Unlike these previous studies, we show that ARF6 can control PI3K expression and, potentially, its catalytic activity.…”

Section: Discussioncontrasting

confidence: 84%

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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Section: Discussioncontrasting

confidence: 84%

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

et al. 2019

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“…This binding was mediated, at least in part, through basic amino acids in the C-terminus of the HVR. PIP5K1A has also been found to associate with other small GTPases (Rac1 and ARF6) 44 , 51 , although Rac1 appears to have the highest affinity 44 .…”

Section: Discussionmentioning

confidence: 99%

Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability

Adhikari

Counter

2018

Nat Commun

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In human cancers, oncogenic mutations commonly occur in the RAS genes KRAS, NRAS, or HRAS, but there are no clinical RAS inhibitors. Mutations are more prevalent in KRAS, possibly suggesting a unique oncogenic activity mediated by KRAS-specific interaction partners, which might be targeted. Here, we determine the specific protein interactomes of each RAS isoform by BirA proximity-dependent biotin identification. The combined interactomes are screened by CRISPR-Cas9 loss-of-function assays for proteins required for oncogenic KRAS-dependent, NRAS-dependent, or HRAS-dependent proliferation and censored for druggable proteins. Using this strategy, we identify phosphatidylinositol phosphate kinase PIP5K1A as a KRAS-specific interactor and show that PIP5K1A binds to a unique region in KRAS. Furthermore, PIP5K1A depletion specifically reduces oncogenic KRAS signaling and proliferation, and sensitizes pancreatic cancer cell lines to a MAPK inhibitor. These results suggest PIP5K1A as a potential target in KRAS signaling for the treatment of KRAS-mutant cancers.

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“…PIP5KIA has been implicated in many cellular processes, including neurite remodeling, cell migration, endocytosis, and phagocytosis, through its production of PI(4,5) P2. 18,21,41,49,[62][63][64][65] Our study adds to the growing repertoire of PIP5K1A functions, showing that PIP5K1A can enhance non-amyloidogenic APP processing. Thus, our data suggest a novel approach to attenuate Aβ production.…”

Section: Discussionmentioning

confidence: 75%

Phosphatidylinositol‐4‐phosphate 5‐kinase type 1α attenuates Aβ production by promoting non‐amyloidogenic processing of amyloid precursor protein

Bhore

Lee

et al. 2020

FASEB j.

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Alzheimer's disease (AD) is characterized by a chronic decline in cognitive function and is pathologically typified by cerebral deposition of amyloid‐β peptide (Aβ). The production of Aβ is mediated by sequential proteolysis of amyloid precursor protein (APP) by β‐ and γ‐secretases, and has been implicated as the essential determinant of AD pathology. Previous studies have demonstrated that the level of phosphatidylinositol‐4,5‐bisphosphate [PI(4,5)P2] in the membrane may potentially modulate Aβ production. Given that PI(4,5)P2 is produced by type 1 phosphatidylinositol‐4‐phosphate 5‐kinases (PIP5Ks), we sought to determine whether the level of PIP5K type Iα (PIP5K1A) can affect production of Aβ by modulating the lipid composition of the membrane. Using a HEK‐derived cell line that constitutively expresses yellow fluorescent protein‐tagged APP (APP‐YFP), we demonstrated that overexpression of PIP5K1A results in significant enhancement of non‐amyloidogenic APP processing and a concomitant suppression of the amyloidogenic pathway, leading to a marked decrease in secreted Aβ. Consistently, cells overexpressing PIP5K1A exhibited a significant redistribution of APP‐YFP from endosomal compartments to the cell surface. Our findings suggest that PIP5K1A may play a critical role in governing Aβ production by modulating membrane distribution of APP, and as such, the pathway may be a valuable therapeutic target for AD.

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Regulation of HGF-induced hepatocyte proliferation by the small GTPase Arf6 through the PIP2-producing enzyme PIP5K1A

Cited by 15 publications

References 30 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

Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability

Phosphatidylinositol‐4‐phosphate 5‐kinase type 1α attenuates Aβ production by promoting non‐amyloidogenic processing of amyloid precursor protein

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