ACAP4 protein cooperates with Grb2 protein to orchestrate epidermal growth factor-stimulated integrin β1 recycling in cell migration.
ARF6 GTPase is an important regulator of membrane trafficking and actin-based cytoskeleton dynamics active at the leading edge of migrating cells. The integrin family heterodimeric transmembrane proteins serve as major receptors for extracellular matrix proteins, which play essential roles in cell adhesion and migration. Our recent proteomic analyses of ARF6 effectors have identified a novel ARF6 GTPase-activating protein, ACAP4, essential for EGF-induced cell migration. However, molecular mechanisms underlying ACAP4-mediated cell migration have remained elusive. Here, we show that ACAP4 regulates integrin β1 dynamics during EGF-stimulated cell migration by interaction with Grb2. Our biochemical study shows that EGF stimulation induces phosphorylation of tyrosine 733, which enables ACAP4 to bind Grb2. This interaction of ACAP4 with Grb2 regulates integrin β1 recycling to the plasma membrane. Importantly, knockdown of ACAP4 by siRNA or overexpression of ACAP4 decreased recycling of integrin β1 to the plasma membrane and reduced integrin-mediated cell migration. Taken together, these results suggest a novel function for ACAP4 in the regulation of cell migration through controlling integrin β1 dynamics.
Anhui Key Laboratory of Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China.
Xue
X
Yu
Anhui Key Laboratory of Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China; Department of Physiology, Morehouse School of Medicine, Atlanta, Georgia 30310. Electronic address: fengsong@ustc.edu.cn.
Fengsong
F
Wang
Anhui Key Laboratory of Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China.
Hongsheng
H
Liu
Department of Physiology, Morehouse School of Medicine, Atlanta, Georgia 30310.
Gregory
G
Adams
Department of Physiology, Morehouse School of Medicine, Atlanta, Georgia 30310.
Felix
F
Aikhionbare
Department of Hepatobiliary Surgery, Xijing Hospital, Xi'an 710032, China.
Dong
D
Liu
Anhui Key Laboratory of Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China; School of Life Sciences, Anhui Medical University, Hefei 230027, China.
Xinwang
X
Cao
School of Life Sciences, Anhui Medical University, Hefei 230027, China.
Libin
L
Fan
Key Laboratory for Stem Cell Biology, SIBS-SJTU Institute of Health Sciences, Shanghai 200025, China.
Guohong
G
Hu
Department of Hepatobiliary Surgery, Xijing Hospital, Xi'an 710032, China.
Yong
Y
Chen
Comprehensive Cancer Center, University of Alabama School of Medicine, Birmingham, Alabama 35294.
Andra
A
Frost
Comprehensive Cancer Center, University of Alabama School of Medicine, Birmingham, Alabama 35294.
Edward
E
Partridge
School of Graduate Studies, Beijing University of Chinese Medicine, Beijing 100029, China.
Xia
X
Ding
Anhui Key Laboratory of Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China; Department of Physiology, Morehouse School of Medicine, Atlanta, Georgia 30310. Electronic address: xyao@msm.edu.
Xuebiao
X
Yao
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000737:chemistry*; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins / Q000737:chemistry; D003599:Cytoskeleton / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D016023:Integrins / Q000737:chemistry; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D014443:Tyrosine / Q000737:chemistry; D000099149:Ezrin
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors; D003598:Cytoskeletal Proteins; D004815:Epidermal Growth Factor; D051380:GRB2 Adaptor Protein; D020690:GTPase-Activating Proteins; D019012:Integrin beta1; D016023:Integrins; D014443:Tyrosine; D000099149:Ezrin; C495948:GRB2 protein, human; C488555:ASAP3 protein, human; C000715348:ARF6 protein, human