Arl4c is a key regulator of tubulogenesis and tumourigenesis as a target gene of Wnt–β-catenin and growth factor–Ras signalling

Matsumoto, Shinji; Fujii, Shinsuke; Kikuchi, Akira

doi:10.1093/jb/mvw069

Cited by 33 publications

(31 citation statements)

References 67 publications

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“…Because ARL4C expression is upregulated by RAS/MAPK signaling, ARL4C signaling may be activated in the early stage of hyperplasia of lung epithelial cells with EGFR or KRAS mutations. ARL4C is a unique small G protein in a constitutively active form irrespective of wild type . Therefore, ARL4C could be active without any active mutations, and its activity could be controlled by quantitative changes through transcriptional upregulation.…”

Section: Discussionmentioning

confidence: 99%

ARL4C is associated with initiation and progression of lung adenocarcinoma and represents a therapeutic target

et al. 2020

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Lung adenocarcinoma is the most common histological type of lung cancer and is classified into adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA). Atypical adenomatous hyperplasia (AAH) lesions are possible precursors to adenocarcinoma. However, the mechanism underlying the stepwise continuum of lung adenocarcinoma is unclear. In this study, the involvement of ADP‐ribosylation factor (ARF)‐like (ARL) 4C (ARL4C), a member of the small GTP‐binding protein family, in the progression of lung adenocarcinoma and the possibility of ARL4C as a molecular target for lung cancer therapy were explored. ARL4C was frequently expressed in AAH and ARL4C expression in immortalized human small airway epithelial cells promoted cell proliferation and suppressed cell death. In addition, ARL4C was expressed with increased frequency in AIS, MIA and IA in a stage‐dependent manner, and the expression was correlated with histologic grade, fluorine‐18 fluorodeoxyglucose uptake and poor prognosis. An anti–sense oligonucleotide (ASO) against ARL4C (ARL4C ASO‐1316) inhibited RAS‐related C3 botulinum toxin substrate activity and nuclear import of Yes‐associated protein and transcriptional coactivator with PDZ‐binding motif, and suppressed in vitro proliferation and migration of lung cancer cells with KRAS or epidermal growth factor receptor (EGFR) mutations. In addition, transbronchial administration of ARL4C ASO‐1316 suppressed orthotopic tumor formation induced by these cancer cells. Thus, ARL4C is involved in the initiation of the premalignant stage and is associated with the stepwise continuum of lung adenocarcinoma. ARL4C ASO‐1316 would be useful for lung adenocarcinoma patients expressing ARL4C regardless of the KRAS or EGFR mutation.

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Section: Discussionmentioning

confidence: 99%

ARL4C is associated with initiation and progression of lung adenocarcinoma and represents a therapeutic target

et al. 2020

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“…ADP-ribosylation factor (ARF)-like proteins (ARL) are one of the subgroups of the ARF family of proteins in the small GTPbinding protein superfamily (5). ARF family proteins are essential regulators of the actin remodeling and membrane-trafficking pathways, including those involved in secretion, endocytosis, and phagocytosis (6).…”

Section: Introductionmentioning

confidence: 99%

Chemically Modified Antisense Oligonucleotide Against ARL4C Inhibits Primary and Metastatic Liver Tumor Growth

Harada

Matsumoto

Hirota

et al. 2019

Molecular Cancer Therapeutics

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ADP-ribosylation factor-like 4c (ARL4C) is identified as a small GTP-binding protein, which is expressed by Wnt and EGF signaling and plays an important role in tubulogenesis of cultured cells and the ureters. ARL4C is little expressed in adult tissues, but it is highly expressed in lung cancer and colorectal cancer and shown to represent a molecular target for cancer therapy based on siRNA experiments. This study revealed that ARL4C is highly expressed in primary hepatocellular carcinoma (HCC) tumors and colorectal cancer liver metastases, and that ARL4C expression is associated with poor prognosis for these cancers. Chemically modified antisense oligonucleotides (ASO) against ARL4C effectively reduced ARL4C expression in both HCC and colorectal cancer cells and inhibited proliferation and migration of these cancer cells in vitro. ARL4C ASOs decreased the PIK3CD mRNA levels and inhibited the activity of AKT in HCC cells, suggesting that the downstream signaling of ARL4C in HCC cells is different from that in lung and colon cancer cells. In addition, subcutaneous injection of ARL4C ASO was effective in reducing the growth of primary HCC and metastatic colorectal cancer in the liver of immunodeficient mice. ARL4C ASO accumulated in cancer cells more efficiently than the surrounding normal cells in the liver and decreased ARL4C expression in the tumor. These results suggest that ARL4C ASO represents a novel targeted nucleic acid medicine for the treatment of primary and metastatic liver cancers.

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“…Different to other Arls and Arfs, Arl4c has a spontaneous GTP binding capability that enables Arl4c to be constantly active (Chiang et al, 2017; Matsumoto et al, 2017). In epithelial cells, Arl4c localizes preferentially at the plasma membrane, where it interacts with cythohesins, or in the nucleus (Hofmann et al, 2007; Matsumoto et al, 2017). Interestingly, our results indicate that Arl4c localizes at the plasma membrane and in punctum in the cytoplasm whereas little Arl4c signal is detected in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

“…Arl4c is a small GTPase that belongs to the A DP- r ibosylation factor (Arf)-like 4 protein sub-family (Arl4) (Matsumoto et al, 2017; Sztul et al, 2019). Despite the high level of Arl4c (also known as Arl7) mRNA detected in human brain tissue, its function in the nervous system remains unknown (Jacobs et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Despite the high level of Arl4c (also known as Arl7) mRNA detected in human brain tissue, its function in the nervous system remains unknown (Jacobs et al, 1999). In epithelial cells, Arl4 proteins participate in actin cytoskeleton rearrangement, vesicle dynamics, and cell migration (Matsumoto et al, 2017). In particular, Arl4c regulates filopodia formation and epithelial cell migration through Cdc42 activation (Chiang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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CRL5-dependent regulation of Arl4c and Arf6 controls hippocampal morphogenesis

Han

Hino

Reyes

et al. 2020

Preprint

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SummaryThe small GTPase Arl4c participates in the regulation of cell migration, cytoskeletal rearrangements, and vesicular trafficking in epithelial cells. The Arl4c signaling cascade starts by the recruitment of the Arf-GEF cytohesins to the plasma membrane, which in turn engage the small GTPase Arf6. In the nervous system, Arf6 regulates dendrite outgrowth in vitro and neuronal migration in the developing cortex. However, the role of Arl4c-cytohesin-Arf6 signaling during brain development and particularly during hippocampal development remain elusive. Here, we report that the E3 ubiquitin ligase Cullin 5/Rbx2 (CRL5) controls the stability of Arl4c and its signaling effectors to regulate hippocampal morphogenesis. Rbx2 knock out causes hippocampal pyramidal neuron mislocalization and formation of multiple apical dendrites. The same phenotypes were observed when Cullin 5 was knocked down in pyramidal neurons by in utero electroporation. We used quantitative mass spectrometry to show that Arl4c, Cytohesin-1/3, and Arf6 accumulate in the telencephalon when Rbx2 is absent. Arl4c expression is post-transcriptionally regulated, with a peak in expression at early postnatal stages, and is localized at the plasma membrane and on intracellular vesicles in hippocampal pyramidal neurons. Furthermore, we show that depletion of Arl4c rescues the phenotypes caused by Cullin 5 knock down in the hippocampus, whereas depletion of Arf6 exacerbates over-migration. Finally, we show that Arl4c and Arf6 are necessary for the dendritic outgrowth of pyramidal neurons to the most superficial strata of the hippocampus. Overall, we identified CRL5 as a key regulator of hippocampal development and uncovered Arl4c and Arf6 as novel CRL5-regulated signaling effectors that control pyramidal neuron migration and dendritogenesis.

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Arl4c is a key regulator of tubulogenesis and tumourigenesis as a target gene of Wnt–β-catenin and growth factor–Ras signalling

Cited by 33 publications

References 67 publications

ARL4C is associated with initiation and progression of lung adenocarcinoma and represents a therapeutic target

ARL4C is associated with initiation and progression of lung adenocarcinoma and represents a therapeutic target

Chemically Modified Antisense Oligonucleotide Against ARL4C Inhibits Primary and Metastatic Liver Tumor Growth

CRL5-dependent regulation of Arl4c and Arf6 controls hippocampal morphogenesis

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