Skip to Main content Skip to Navigation
Journal articles

KIT mutations induce intracellular retention and activation of an immature form of the KIT protein in gastrointestinal stromal tumors.

Abstract : PURPOSE: Gastrointestinal stromal tumors (GIST) are frequently associated with gain-of-function mutations of KIT, which can be inhibited by imatinib both in vitro and in vivo. The survival of patients with GIST, following imatinib therapy, has been correlated with the nature of mutations but not with KIT expression. EXPERIMENTAL DESIGN: Subcellular localization, activation, and trafficking of the mature and the immature forms of KIT were investigated in GIST samples and in NIH3T3 cells infected with two different GIST-type exon 11-mutated human KIT cDNA. RESULTS: Paranuclear dot expression of KIT was more frequent in GISTs with homozygous KIT mutations than in those with heterozygous (P = 0.01) or no mutations (P < 0.01). Activation of the immature 125 kDa form of KIT was detected in most GISTs with KIT mutations but not in GISTs without KIT mutations. In NIH3T3 cells, mutant KIT was mainly retained within endoplasmic reticulum and Golgi compartments in an immature constitutively phosphorylated form, whereas the wild-type KIT was expressed at the plasma membrane, in a mature nonphosphorylated form. Imatinib-induced inhibition of the phosphorylation of immature and mature mutant KIT proteins resulted in the restoration of KIT expression at the cell surface. CONCLUSIONS: These results show that GIST-type KIT mutations induce an activation-dependent alteration of normal maturation and trafficking, resulting in the intracellular retention of the activated kinase within the cell. These observations likely account for the absence of correlation between response to imatinib and KIT expression using immunohistochemistry and may deserve to be investigated in other tyrosine kinase-activated tumors.
Document type :
Journal articles
Complete list of metadatas

https://hal.archives-ouvertes.fr/hal-00283136
Contributor : Corinne Brachet-Ducos <>
Submitted on : Thursday, May 29, 2008 - 10:37:45 AM
Last modification on : Wednesday, October 14, 2020 - 4:08:16 AM

Links full text

Identifiers

Collections

Citation

Séverine Tabone-Eglinger, Frédéric Subra, Hiba El Sayadi, Laurent Alberti, Eric Tabone, et al.. KIT mutations induce intracellular retention and activation of an immature form of the KIT protein in gastrointestinal stromal tumors.. Clinical Cancer Research, American Association for Cancer Research, 2008, 14 (8), pp.2285-94. ⟨10.1158/1078-0432.CCR-07-4102⟩. ⟨hal-00283136⟩

Share

Metrics

Record views

247