title: Pincher, a pinocytic chaperone for nerve growth factor/TrkA signaling endosomes.
abstract: 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.
authors: Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
authors: Yufang
authors: Y
authors: Shao
authors: Wendy
authors: W
authors: Akmentin
authors: Juan Jose
authors: JJ
authors: Toledo-Aral
authors: Julie
authors: J
authors: Rosenbaum
authors: Gregorio
authors: G
authors: Valdez
authors: John B
authors: JB
authors: Cabot
authors: Brian S
authors: BS
authors: Hilbush
authors: Simon
authors: S
authors: Halegoua
mesh_terms: 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
chemical_list: C456611:Ehd4 protein, rat; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020928:Mitogen-Activated Protein Kinases