ADP-ribosylation factor 6(Arf6),a small G-protein of the Ras superfamily,plays pivotal roles in multiple cellular events,including exocytosis,endocytosis,actin remodeling,plasma membrane reorganization and vesicular t...ADP-ribosylation factor 6(Arf6),a small G-protein of the Ras superfamily,plays pivotal roles in multiple cellular events,including exocytosis,endocytosis,actin remodeling,plasma membrane reorganization and vesicular transport.Arf6 regulates the progression of cancer through the activation of cell motility and invasion.Aberrant Arf6 activation is a potential therapeutic target.This review aims to understand the comprehensive function of Arf6 for future cancer therapy.The Arf6 GEFs,protein structure,and roles in cancer have been summarized.Comprehending the mechanism underlying Arf6-mediated cancer cell growth and survival is essential.The structural features of Arf6 and its efforts are discussed and may be contributed to the discovery of future novel protein-protein interaction inhibitors.In addition,Arf6 inhibitors and mechanism of action are listed in the table.This review further emphasizes the crucial roles in drug resistance and attempts to offer an outlook of Arf6 in cancer therapy.展开更多
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
基金the National Natural Science Foundation of China(NSFC)(No.81773594,82204224)Chunhui Program-Cooperative Research Project of the Ministry of Education+3 种基金Liaoning Province Natural Science Foundation(No.2022-MS241,China)China Postdoctoral Science Foundation(No.2021M693957,China)Shenyang Young and Middle-aged Innovative Talents Support Program(RC210446,China)Project of the Educational Department of Liaoning Province(No.LJKZ0919,China),for financial supports。
文摘ADP-ribosylation factor 6(Arf6),a small G-protein of the Ras superfamily,plays pivotal roles in multiple cellular events,including exocytosis,endocytosis,actin remodeling,plasma membrane reorganization and vesicular transport.Arf6 regulates the progression of cancer through the activation of cell motility and invasion.Aberrant Arf6 activation is a potential therapeutic target.This review aims to understand the comprehensive function of Arf6 for future cancer therapy.The Arf6 GEFs,protein structure,and roles in cancer have been summarized.Comprehending the mechanism underlying Arf6-mediated cancer cell growth and survival is essential.The structural features of Arf6 and its efforts are discussed and may be contributed to the discovery of future novel protein-protein interaction inhibitors.In addition,Arf6 inhibitors and mechanism of action are listed in the table.This review further emphasizes the crucial roles in drug resistance and attempts to offer an outlook of Arf6 in cancer therapy.
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.
