title: Phosphorylation of the Bin, Amphiphysin, and RSV161/167 (BAR) domain of ACAP4 regulates membrane tubulation.
abstract: ArfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 4 (ACAP4) is an ADP-ribosylation factor 6 (ARF6) GTPase-activating protein essential for EGF-elicited cell migration. However, how ACAP4 regulates membrane dynamics and curvature in response to EGF stimulation is unknown. Here, we show that phosphorylation of the N-terminal region of ACAP4, named the Bin, Amphiphysin, and RSV161/167 (BAR) domain, at Tyr34 is necessary for EGF-elicited membrane remodeling. Domain structure analysis demonstrates that the BAR domain regulates membrane curvature. EGF stimulation of cells causes phosphorylation of ACAP4 at Tyr34, which subsequently promotes ACAP4 homodimer curvature. The phospho-mimicking mutant of ACAP4 demonstrates lipid-binding activity and tubulation in vitro, and ARF6 enrichment at the membrane is associated with ruffles of EGF-stimulated cells. Expression of the phospho-mimicking ACAP4 mutant promotes ARF6-dependent cell migration. Thus, the results present a previously undefined mechanism by which EGF-elicited phosphorylation of the BAR domain controls ACAP4 molecular plasticity and plasma membrane dynamics during cell migration.
authors.affiliation: Anhui Key Laboratory of Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Xuannv
authors.initials: X
authors.lastname: Zhao
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wang
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.forename: Lifang
authors.initials: L
authors.lastname: Liu
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Song
authors.forename: Tongge
authors.initials: T
authors.lastname: Zhu
authors.forename: Gregory
authors.initials: G
authors.lastname: Adams
authors.forename: Xinjiao
authors.initials: X
authors.lastname: Gao
authors.forename: Ruijun
authors.initials: R
authors.lastname: Tian
authors.forename: Yuejia
authors.initials: Y
authors.lastname: Huang
authors.forename: Runhua
authors.initials: R
authors.lastname: Chen
authors.forename: Fengsong
authors.initials: F
authors.lastname: Wang
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.forename: Xue
authors.initials: X
authors.lastname: Yu
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Zhengjun
authors.initials: Z
authors.lastname: Chen
authors.forename: Maikun
authors.initials: M
authors.lastname: Teng
authors.forename: Xia
authors.initials: X
authors.lastname: Ding
authors.forename: Xuebiao
authors.initials: X
authors.lastname: Yao
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D000595:Amino Acid Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics; D004815:Epidermal Growth Factor / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology
chemical_list: D000089982:ADP-Ribosylation Factor 6; D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D020690:GTPase-Activating Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C075637:amphiphysin; D004815:Epidermal Growth Factor; C488555:ASAP3 protein, human; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human