Crosstalk between CLCb/Dyn1-Mediated Adaptive Clathrin-Mediated Endocytosis and Epidermal Growth Factor Receptor Signaling Increases Metastasis.
Signaling receptors are internalized and regulated by clathrin-mediated endocytosis (CME). Two clathrin light chain isoforms, CLCa and CLCb, are integral components of the endocytic machinery whose differential functions remain unknown. We report that CLCb is specifically upregulated in non-small-cell lung cancer (NSCLC) cells and is associated with poor patient prognosis. Engineered single CLCb-expressing NSCLC cells, as well as "switched" cells that predominantly express CLCb, exhibit increased rates of CME and altered clathrin-coated pit dynamics. This "adaptive CME" resulted from upregulation of dynamin-1 (Dyn1) and its activation through a positive feedback loop involving enhanced epidermal growth factor (EGF)-dependent Akt/GSK3β phosphorylation. CLCb/Dyn1-dependent adaptive CME selectively altered EGF receptor trafficking, enhanced cell migration in vitro, and increased the metastatic efficiency of NSCLC cells in vivo. We define molecular mechanisms for adaptive CME in cancer cells and a role for the reciprocal crosstalk between signaling and CME in cancer progression.
Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: ping-hung.chen@utsouthwestern.edu.
Ping-Hung
PH
Chen
Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Nawal
N
Bendris
Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei 10617, Taiwan.
Yi-Jing
YJ
Hsiao
Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Carlos R
CR
Reis
Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Marcel
M
Mettlen
Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan.
Hsuan-Yu
HY
Chen
Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei 10617, Taiwan.
Sung-Liang
SL
Yu
Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: sandra.schmid@utsouthwestern.edu.
Sandra L
SL
Schmid
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002966:Clathrin / Q000378:metabolism*; D033941:Clathrin Light Chains / Q000378:metabolism*; D003034:Coated Pits, Cell-Membrane / Q000378:metabolism; D034284:Dynamin I / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D016019:Survival Analysis; D015854:Up-Regulation / Q000235:genetics
C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002966:Clathrin; D033941:Clathrin Light Chains; D066246:ErbB Receptors; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D034284:Dynamin I
Akt/GSK3β signaling; cell migration; clathrin light chain; clathrin-mediated endocytosis; dynamin-1; metastasis; non-small-cell lung cancer (NSCLC); receptor recycling