ADP-ribosylation factor–like 4A interacts with Robo1 to promote cell migration by regulating Cdc42 activation

Chiang, Tsai-Shin; Lin, Michael C.; Tsai, Meng-Chen; Chen, Chieh-Hsin; Jang, Li-Ting; Lee, Fang‐Jen S.

doi:10.1091/mbc.e18-01-0001

Cited by 13 publications

(15 citation statements)

References 42 publications

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“…We also found significantly increased expression of Arf-like (Arl) genes including Arl11, which belong to another family of small GTPases and are involved in regulation of vesicular transport, membrane trafficking, and cytoskeletal remodeling ( 68 ). The GTP-GDP cycle in small GTPases is tightly regulated by guanine nucleotide exchange factors (GEFs) ( 69 ). We identified significant changes in GEF expression, which are involved in regulating GTPases and thus downstream MV shedding.…”

Section: Discussionmentioning

confidence: 99%

Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients

et al. 2020

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Initially underestimated as platelet dust, extracellular vesicles are continuously gaining interest in the field of inflammation. Various studies addressing inflammatory diseases have shown that microvesicles (MVs) originating from different cell types are systemic transport vehicles carrying distinct cargoes to modulate immune responses. In this study, we focused on the clinical setting of multiple trauma, which is characterized by activation and dysfunction of both, the fluid-phase and the cellular component of innate immunity. Given the sensitivity of neutrophils for the complement anaphylatoxin C5a, we hypothesized that increased C5a production induces alterations in MV shedding of neutrophils resulting in neutrophil dysfunction that fuels posttraumatic inflammation. In a mono-centered prospective clinical study with polytraumatized patients, we found significantly increased granulocyte-derived MVs containing the C5a receptor (C5aR1, CD88) on their surface. This finding was accompanied by a concomitant loss of C5aR1 on granulocytes indicative of an impaired cellular chemotactic and pro-inflammatory neutrophil functions. Furthermore, in vitro exposure of human neutrophils (from healthy volunteers) to C5a significantly increased MV shedding and C5aR1 loss on neutrophils, which could be blocked using the C5aR1 antagonist PMX53. Mechanistic analyses revealed that the interaction between C5aR1 signaling and the small GTPase Arf6 acts as a molecular switch for MV shedding. When neutrophil derived, C5a-induced MV were exposed to a complex ex vivo whole blood model significant pro-inflammatory properties (NADPH activity, ROS and MPO generation) of the MVs became evident. C5a-induced MVs activated resting neutrophils and significantly induced IL-6 secretion. These data suggest a novel role of the C5a-C5aR1 axis: C5a-induced MV shedding from neutrophils results in decreased C5aR1 surface expression on the one hand, on the other hand it leads to profound inflammatory signals which likely are both key drivers of the neutrophil dysfunction which is regularly observed in patients suffering from multiple traumatic injuries.

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Section: Discussionmentioning

confidence: 99%

Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients

et al. 2020

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“…A previous study showed that Nck bound to the Robo1 receptor recruits Pak to specific sites at the growth cone membrane (Fan et al, 2003). To test whether Arl4A-induced Pak1 membrane localization occurs through the Robo1-Nck-Pak1 interaction, we used shRNA to knockdown Robo1 (Chiang et al, 2019), but did not observe impaired Arl4Ainduced Pak1 PM localization ( Fig. S4D).…”

Section: Pak1 Recruits Cytoplasmic Myristoylation-deficient Arl4a To mentioning

confidence: 89%

“…Previous studies have shown that Arl4a mRNA is specifically upregulated in hepatocyte growth factor-stimulated polarized MDCK cells (Balkovetz et al, 2004), SW620 metastatic colorectal cancer cells, and in the process of monocyte differentiation (Kubosaki et al, 2009). Additionally, our recent study showed that Arl4A participates in Slit2/Robo1 signaling to modulate cell motility (Chiang et al, 2019); however, evidence of the function of Arl4A in cell migration is insufficient.…”

Section: Introductionmentioning

confidence: 87%

“…For example, Arl4A directly interacts with the golgin GCC185 (GCC2) through the Rab-binding domain and participates in the function of GCC185 to maintain Golgi structure and endosome-to-Golgi transport (Lin et al, 2011). Arl4A also complexes with ELMO/DOCK180 to regulate membrane protrusion and the actin cytoskeleton (Chiang et al, 2019). In addition to localizing to the cytosol and plasma membrane (PM), Arl4A also localizes to endosomes, Golgi and the nucleus (Lin et al, 2000(Lin et al, , 2011.…”

Section: Introductionmentioning

confidence: 99%

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Cooperative recruitment of Arl4A and Pak1 to the plasma membrane contributes to sustained Pak1 activation for cell migration

Chen

Chiang

et al. 2020

Journal of Cell Science

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Cell migration requires the coordination of multiple signaling pathways involved in membrane dynamics and cytoskeletal rearrangement. The Arf-like small GTPase Arl4A has been shown to modulate actin cytoskeleton remodeling. However, evidence of the function of Arl4A in cell migration is insufficient. Here, we report that Arl4A acts with the serine/threonine protein kinase Pak1 to modulate cell migration through their cooperative recruitment to the plasma membrane. We first observed that Arl4A and its isoform Arl4D interact with Pak1 and Pak2 and showed that Arl4A recruits Pak1 and Pak2 to the plasma membrane. The fibronectin-induced Pak1 localization at the plasma membrane is reduced in Arl4A-depleted cells. Unexpectedly, we found that Pak1, but not Arl4A-binding-defective Pak1, can recruit a cytoplasmic myristoylation-deficient Arl4A-G2A mutant to the plasma membrane. Furthermore, we found that the Arl4A-Pak1 interaction, which is independent of Rac1 binding to Pak1, is required for Arl4A-induced cell migration. Thus, we infer that there is feedback regulation between Arl4A and Pak1, in which they mutually recruit each other to the plasma membrane for Pak1 activation, thereby modulating cell migration through direct interaction.

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“…ARL8B is essential for the 3D invasive growth of prostate cancer both in vitro and in vivo (9). ARL4A could interact with Robo1 to promote cell migration by activating Cdc42 (10). A recent study reveals that ARL13B can enhance the migration and invasion of breast cancer cells via controlling integrin-mediated signaling pathway (11).…”

Section: Introductionmentioning

confidence: 99%

ARL4C is A Key Driver of Gastric Cancer: An Integrative Analysis of ARL Family Members

Xie¹,

Bai²,

Lu³

et al. 2020

Preprint

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Background: As small GTP-binding proteins, ARL family members (ARLs) have been proved to regulate the malignant phenotypes of several cancers. However, the exact role of ARLs in gastric cancer (GC) remains elusive.Methods: The expression status, interactive relations, potential pathways and genetic variations of ARLs are analyzed by bioinformatics tools. Machine learning models and enrichment analysis are performed by R platform. The biological functions of ARL4C are demonstrated by in vitro and in vivo experiments. The nomogram is further constructed to validate the prognostic value of ARL4C for GC patients.Results: ARLs are significantly dysregulated in GC and involved in various cancer-related pathways. Subsequently, machine learning models identify ARL4C as one of the two most significant diagnostic and prognostic indicators among ARLs for GC. Furthermore, ARL4C silencing remarkably reverses the epithelial-mesenchymal transition (EMT) and inhibits the growth and metastasis of GC cells both in vitro and in vivo. Moreover, enrichment analysis indicates that TGF-β1 is highly correlated with ARL4C, while ARL4C-related genes are significantly enriched in the TGF-β1 signaling. Correspondingly, we demonstrate that TGF-β1 treatment dramatically increases ARL4C expression, and ARL4C knockdown reverses TGF-β1-induced EMT possibly by inhibiting the expression of Smads, downstream factors of TGF-β1. Meanwhile, the coexpression of ARL4C and TGF-β1 worsens the prognosis of GC patients both in Kaplan-Meier analysis and nomogram model.Conclusion: Our work is of significance for comprehensively understanding the crucial role of ARLs in the carcinogenesis of GC and the specific mechanisms underlying the GC-promoting effects of TGF-β1. More importantly, we uncover the great promise of ARL4C-targeted therapy in improving the efficacy of TGF-β1 inhibitors for GC patients.

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ADP-ribosylation factor–like 4A interacts with Robo1 to promote cell migration by regulating Cdc42 activation

Cited by 13 publications

References 42 publications

Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients

Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients

Cooperative recruitment of Arl4A and Pak1 to the plasma membrane contributes to sustained Pak1 activation for cell migration

ARL4C is A Key Driver of Gastric Cancer: An Integrative Analysis of ARL Family Members

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