title: Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling.
abstract: Nerve growth factor (NGF) binding to p75(NTR) influences TrkA signaling, yet the molecular mechanism is unknown. We observe that NGF stimulates TrkA polyubiquitination, which was attenuated in p75(-/-) mouse brain. TrkA is a substrate of tumor necrosis factor receptor-associated factor 6 (TRAF6), and expression of K63R mutant ubiquitin or an absence of TRAF6 abrogated TrkA polyubiquitination and internalization. NGF stimulated formation of a TrkA/p75(NTR) complex through the p62 scaffold, recruiting the E3/TRAF6 and E2/UbcH7. Peptide targeted to the TRAF6 binding site present in p62 blocked interaction with TRAF6 and inhibited ubiquitination of TrkA, signaling, internalization, and NGF-dependent neurite outgrowth. Mutation of K485 to R blocked TRAF6 and NGF-dependent polyubiquitination of TrkA, resulting in retention of the receptor on the membrane and an absence in activation of specific signaling pathways. These findings reveal that polyubiquitination serves as a common platform for the control of receptor internalization and signaling.
authors.affiliation: Department of Biological Sciences, Program in Cellular and Molecular Biosciences, Auburn University, Auburn, Alabama 36849, USA.
authors.forename: Thangiah
authors.initials: T
authors.lastname: Geetha
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Jiang
authors.forename: Marie W
authors.initials: MW
authors.lastname: Wooten
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D016716:PC12 Cells; D025821:Polyubiquitin / Q000378:metabolism*; D051381:Rats; D020917:Receptor, trkA / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
chemical_list: D009414:Nerve Growth Factors; D048029:TNF Receptor-Associated Factor 6; D025821:Polyubiquitin; D020917:Receptor, trkA; D008239:Lysine