title: Ligand-induced downregulation of TrkA is partly regulated through ubiquitination by Cbl.
abstract: Nerve growth factor (NGF) binding to its receptor TrkA, which belongs to the family of receptor tyrosine kinases (RTKs), is known to induce its internalization, endosomal trafficking and subsequent lysosomal degradation. The Cbl family of ubiquitin ligases plays a major role in mediating ubiquitination and degradation of RTKs. However, it is not known whether Cbl participates in mediating ubiquitination of TrkA. Here we report that c-Cbl mediates ligand-induced ubiquitination and degradation of TrkA. TrkA ubiquitination and degradation required direct interactions between c-Cbl and phosphorylated TrkA. c-Cbl and ubiquitinated TrkA are found in a complex after NGF stimulation and are degraded in lysosomes. Taken together, our data demonstrate that c-Cbl can induce downregulation of NGF-TrkA complexes through ubiquitination and degradation of TrkA.
authors.affiliation: Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Yuga
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Noriaki
authors.initials: N
authors.lastname: Shimokawa
authors.forename: Saeed
authors.initials: S
authors.lastname: Esmaeili-Mahani
authors.forename: Akihito
authors.initials: A
authors.lastname: Morita
authors.forename: Hiroko
authors.initials: H
authors.lastname: Masuda
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Jun'ichi
authors.initials: J
authors.lastname: Tamura
authors.forename: Kaisa
authors.initials: K
authors.lastname: Haglund
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Koibuchi
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D020932:Nerve Growth Factor / Q000378:metabolism; D010766:Phosphorylation; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D008024:Ligands; D020932:Nerve Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; D020917:Receptor, trkA