Pincher, a pinocytic chaperone for nerve growth factor/TrkA signaling endosomes.
A central tenet of nerve growth factor (NGF) action that is poorly understood is its ability to mediate cytoplasmic signaling, through its receptor TrkA, that is initiated at the nerve terminal and conveyed to the soma. We identified an NGF-induced protein that we termed Pincher (pinocytic chaperone) that mediates endocytosis and trafficking of NGF and its receptor TrkA. In PC12 cells, overexpression of Pincher dramatically stimulated NGF-induced endocytosis of TrkA, unexpectedly at sites of clathrin-independent macropinocytosis within cell surface ruffles. Subsequently, a system of Pincher-containing tubules mediated the delivery of NGF/TrkA-containing vesicles to cytoplasmic accumulations. These vesicles selectively and persistently mediated TrkA-erk5 mitogen-activated protein kinase signaling. A dominant inhibitory mutant form of Pincher inhibited the NGF-induced endocytosis of TrkA, and selectively blocked TrkA-mediated cytoplasmic signaling of erk5, but not erk1/2, kinases. Our results indicate that Pincher mediates pinocytic endocytosis of functionally specialized NGF/TrkA endosomes with persistent signaling potential.
Shao
Yufang
Y
Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
Akmentin
Wendy
W
Toledo-Aral
Juan Jose
JJ
Rosenbaum
Julie
J
Valdez
Gregorio
G
Cabot
John B
JB
Hilbush
Brian S
BS
Halegoua
Simon
S
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D005110:Extracellular Space / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology; D008854:Microscopy, Electron; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000302:isolation & purification*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020932:Nerve Growth Factor / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000302:isolation & purification*; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D016716:PC12 Cells; D010766:Phosphorylation; D010873:Pinocytosis / Q000502:physiology*; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D022161:Transport Vesicles / Q000378:metabolism / Q000648:ultrastructure
C456611:Ehd4 protein, rat; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020928:Mitogen-Activated Protein Kinases