Tumor metastasis represents the main causes of cancer-related death.Our recent study showed that chemokine CCL18 secreted from tumor-associated macrophages regulates breast tumor metastasis,but the underlying mechanis...Tumor metastasis represents the main causes of cancer-related death.Our recent study showed that chemokine CCL18 secreted from tumor-associated macrophages regulates breast tumor metastasis,but the underlying mechanisms remain less clear.Here, we show that ARF6 GTPase-activating protein ACAP4 regulates CCL18-elicited breast cancer cell migration via the acetyltransferase PCAF-mediated acetylation.CCL18 stimulation elicited breast cancer cell migration and invasion via PCAF-dependent acetylation.ACAP4 physically interacts with PCAF and is a cognate substrate of PCAF during CCL18 stimulation.The acetylation site of ACAP4 by PCAF was mapped to Lys311 by mass spectrometric analyses.Importantly,dynamic acetylation of ACAP4 is essential for CCL18-induced breast cancer cell migration and invasion,as overexpression of the persistent acetylation-mimicking or nonacetylatable ACAP4 mutant blocked CCL18-elicited cell migration and invasion.Mechanistically,the acetylation of ACAP4 at Lys311 reduced the lipid-binding activity of ACAP4 to ensure a robust and dynamic cycling of ARF6-ACAP4 complex with plasma membrane in response to CCL18 stimulation.Thus,these results present a previously undefined mechanism by which CCL18-elicited acetylation of the PH domain controls dynamic interaction between ACAP4 and plasma membrane during breast cancer cell migration and invasion.展开更多
Cell migration requires the generation of branched actin networks and recruitment of vesicular membrane that power the protrusion of the plasma membrane in lamellipodia.However,the molecular mechanisms underlying dyna...Cell migration requires the generation of branched actin networks and recruitment of vesicular membrane that power the protrusion of the plasma membrane in lamellipodia.However,the molecular mechanisms underlying dynamic recruitment of vesicular membrane during cell migration remain elusive.Here,we report a critical mechanism underlying epidermal growth factor(EGF)-elicited Akt signaling-steered cell migration.Using functional proteomics screen,we identified a novel ADP-ribosylation factor 6(ARF6)–ACAP4 signaling regulator,Acapin,which inhibits the GTPase-activating protein(GAP)activity of ACAP4 to activate ARF6 GTPase in vitro.In cells,EGF stimulation elicits Akt signaling,which recruits Acapin to the lamellipodium membrane via phosphorylation of Acapin at its Ser247 residue and enhances the binding of Acapin to ACAP4 to elevate the ARF6-GTP level.Therefore,Acapin is required for efficiently stimulating cell migration by EGF–Akt signaling.Together,our results demonstrate the role of Acapin in relaying the Akt signaling cascade during cell migration processes.展开更多
基金the National Natural Science Foundation of China (31430054,31621002,31320103904, 81630080,31671405,31471275,and 31501130)the National Key Research and Development Program of China (2017YFA0503600,2016YFA0100500,and 2016YFA0101202)+3 种基金the Ministry of Education (IRT_17R102,20113402130010)the Strategic Priority Research Program of Chinese Academy of Sciences (XDB19000000)National Institutes of Health Grants (CA 164133,DK115812,and DK56292)Central University Grants (WK2070000066).
文摘Tumor metastasis represents the main causes of cancer-related death.Our recent study showed that chemokine CCL18 secreted from tumor-associated macrophages regulates breast tumor metastasis,but the underlying mechanisms remain less clear.Here, we show that ARF6 GTPase-activating protein ACAP4 regulates CCL18-elicited breast cancer cell migration via the acetyltransferase PCAF-mediated acetylation.CCL18 stimulation elicited breast cancer cell migration and invasion via PCAF-dependent acetylation.ACAP4 physically interacts with PCAF and is a cognate substrate of PCAF during CCL18 stimulation.The acetylation site of ACAP4 by PCAF was mapped to Lys311 by mass spectrometric analyses.Importantly,dynamic acetylation of ACAP4 is essential for CCL18-induced breast cancer cell migration and invasion,as overexpression of the persistent acetylation-mimicking or nonacetylatable ACAP4 mutant blocked CCL18-elicited cell migration and invasion.Mechanistically,the acetylation of ACAP4 at Lys311 reduced the lipid-binding activity of ACAP4 to ensure a robust and dynamic cycling of ARF6-ACAP4 complex with plasma membrane in response to CCL18 stimulation.Thus,these results present a previously undefined mechanism by which CCL18-elicited acetylation of the PH domain controls dynamic interaction between ACAP4 and plasma membrane during breast cancer cell migration and invasion.
基金supported by grants from the Ministry of Science and Technology of China and the National Natural Science Foundationof China(2022YFA1303100,32090040,92254302,91953000,32300649,32400593,32170737,31501130,91854203,31621002,and 2017YFA0503600)the Ministry of Education(IRT_17R102)+1 种基金the Fundamental Research Funds for the Central Universities(KB910000oo07,KB9100000006,and KB9100000013)Plans for Major Provincial Science&Technology Projects of Anhui Province(202303a0702003).
文摘Cell migration requires the generation of branched actin networks and recruitment of vesicular membrane that power the protrusion of the plasma membrane in lamellipodia.However,the molecular mechanisms underlying dynamic recruitment of vesicular membrane during cell migration remain elusive.Here,we report a critical mechanism underlying epidermal growth factor(EGF)-elicited Akt signaling-steered cell migration.Using functional proteomics screen,we identified a novel ADP-ribosylation factor 6(ARF6)–ACAP4 signaling regulator,Acapin,which inhibits the GTPase-activating protein(GAP)activity of ACAP4 to activate ARF6 GTPase in vitro.In cells,EGF stimulation elicits Akt signaling,which recruits Acapin to the lamellipodium membrane via phosphorylation of Acapin at its Ser247 residue and enhances the binding of Acapin to ACAP4 to elevate the ARF6-GTP level.Therefore,Acapin is required for efficiently stimulating cell migration by EGF–Akt signaling.Together,our results demonstrate the role of Acapin in relaying the Akt signaling cascade during cell migration processes.
