The aberrant localization of oncogenic kit tyrosine kinase receptor mutants is reversed on specific inhibitory treatment. - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Molecular Cancer Research Année : 2009

The aberrant localization of oncogenic kit tyrosine kinase receptor mutants is reversed on specific inhibitory treatment.

Résumé

Kit is a cell surface type III tyrosine kinase (TK) receptor implicated in cell transformation through overexpression or oncogenic mutation. Two categories of Kit mutants displaying mutations either in the juxtamembrane intracellular domain (regulatory mutants) or in the catalytic domain (catalytic mutants) have been described. To explore the effect of Kit oncogenic mutations on its subcellular localization, we constructed enhanced green fluorescent protein (EGFP)-tagged human Kit chimeras harboring mutations either in the regulatory (V560G) or in the catalytic (D816V) domain. When expressed in Chinese hamster ovary cells, EGFP-tagged wild-type Kit was activated on stem cell factor stimulation, whereas both EGFP-tagged Kit mutants displayed a constitutive TK activity. Constitutively activated mutants exhibited a high-mannose-type N-glycosylation pattern and an intracellular localization, suggesting that these mutants induce downstream oncogenic signaling without the need to reach the cell surface. Inhibition of constitutive Kit TK activity with dasatinib induced a complex, mature N-glycosylation pattern identical to unstimulated wild-type Kit and resulted in the redistribution of the mutants to the plasma membrane. This relocalization was clearly correlated to the inhibition of TK activity because imatinib, a specific inhibitor of the V560G mutant, inactive on the catalytic D816V mutant, induced only the relocalization of the V560G mutant. These data show that on TK inhibition, the aberrant localization of Kit mutants can be fully reversed. Kit mutants are then exported and/or stabilized at the cell surface as inactive and fully N-glycosylated isoforms.

Domaines

Biophysique
Fichier non déposé

Dates et versions

hal-00421163 , version 1 (01-10-2009)

Identifiants

Citer

Houcine Bougherara, Frédéric Subra, Ronan Crépin, Patrick Tauc, Christian Auclair, et al.. The aberrant localization of oncogenic kit tyrosine kinase receptor mutants is reversed on specific inhibitory treatment.. Molecular Cancer Research, 2009, 7 (9), pp.1525-33. ⟨10.1158/1541-7786.MCR-09-0138⟩. ⟨hal-00421163⟩
36 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More