Ligand-induced downregulation of TrkA is partly regulated through ubiquitination by Cbl

• Published in: FEBS letters Vol. 585; no. 12; pp. 1741 - 1747
• Main Authors: Takahashi, Yuga, Shimokawa, Noriaki, Esmaeili-Mahani, Saeed, Morita, Akihito, Masuda, Hiroko, Iwasaki, Toshiharu, Tamura, Jun’ichi, Haglund, Kaisa, Koibuchi, Noriyuki
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 23.06.2011
• Subjects: Animals; c-Cbl; Cell Line; Down-Regulation - drug effects; Humans; Ligands; Lysosomes - metabolism; Mice; Nedd4-2; Nerve Growth Factor - metabolism; Phosphorylation; Proto-Oncogene Proteins c-cbl - metabolism; Rats; Receptor, trkA - metabolism; TrkA degradation; Ubiquitination; Ubiquitination - physiology; TrkA degradation; Ubiquitination; c-Cbl; Nedd4-2
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2011.04.056

► c-Cbl can promote ligand-induced ubiquitination and consequent degradation of TrkA. ► TrkA ubiquitination and degradation required direct interactions between c-Cbl and phosphorylated TrkA. ► c-Cbl can induce downregulation of NGF-TrkA complexes through ubiquitination and degradation of TrkA. ► c-Cbl has little effect on the internalization of TrkA. 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. TrkAphysically interacts with c-Cbl by anti bait coimmunoprecipitation(View interaction) c-Cblphysically interacts with TrkA by anti bait coimmunoprecipitation(View interaction)