Geldanamycins trigger a novel Ron degradative pathway, hampering oncogenic signaling.
Ron, the tyrosine kinase receptor for macrophage-stimulating protein is responsible for proliferation and migration of cells from different tissues. Ron can acquire oncogenic potential by single point mutations in the kinase domain, and dysregulated Ron signaling has been involved in the development of different human cancers. We have previously shown that ligand-activated Ron recruits the negative regulator c-Cbl, which mediates its ubiquitylation and degradation. Here we report that Ron is ubiquitylated also by the U-box E3 ligase C-terminal Hsc70-interacting protein (CHIP), recruited via chaperone intermediates Hsp90 and Hsc70. Gene silencing shows that CHIP activity is necessary to mediate Ron degradation upon cell treatment with Hsp90 inhibitors geldanamycins. The oncogenic Ron(M1254T) receptor escapes from c-Cbl negative regulation but retains a strong association with CHIP. This constitutively active mutant of Ron displays increased sensitivity to geldanamycins, enhanced physical interaction with Hsp90, and more rapid degradation rate. Cell growth and migration, as well as the transforming potential evoked by Ron(M1254T), are abrogated upon Hsp90 inhibition. These data highlight a novel mechanism for Ron degradation and propose Hsp90 antagonists like geldanamycins as suitable pharmacological agents for therapy of cancers where altered Ron signaling is involved.
Germano
Serena
S
Department DISCAFF and DFB Center, University of Piemonte Orientale "A. Avogadro," Novara 28100, Italy.
Barberis
Davide
D
Department DISCAFF and DFB Center, University of Piemonte Orientale "A. Avogadro," Novara 28100, Italy.
Santoro
Massimo M
MM
Department DISCAFF and DFB Center, University of Piemonte Orientale "A. Avogadro," Novara 28100, Italy.
Penengo
Lorenza
L
Department DISCAFF and DFB Center, University of Piemonte Orientale "A. Avogadro," Novara 28100, Italy.
Citri
Ami
A
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
Yarden
Yosef
Y
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
Gaudino
Giovanni
G
Department DISCAFF and DFB Center, University of Piemonte Orientale "A. Avogadro," Novara 28100, Italy. Electronic address: giovanni.gaudino@unipmn.it.
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D019556:COS Cells; D002465:Cell Movement; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051379:Mice; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D009369:Neoplasms; D050721:Proto-Oncogene Proteins c-cbl; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D050721:Proto-Oncogene Proteins c-cbl; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; C493849:Cbl protein, mouse; C001277:geldanamycin