Signal transduction by several KIT juxtamembrane domain mutations

Castéran, Nathalie; Sepulveda, Paulo De; Beslu, Nathalie; Aoubala, Mustapha; Letard, Sébastien; Lecocq, Eric; Rottapel, Robert; Dubreuil, Patrice

doi:10.1038/sj.onc.1206587

Cited by 66 publications

(63 citation statements)

References 49 publications

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“…[45][46][47][48][49][50] The importance of the JM domain in signaling is evident from several mutations, deletions and insertions in this domain that can lead to cancer. [51][52][53] In addition, recent studies have provided evidence for the active role of the JM domains in regulating RTK activity.…”

Section: Juxtamembrane Domainsmentioning

confidence: 99%

Receptor tyrosine kinase transmembrane domains

Hristova

2010

Cell Adhesion & Migration

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Section: Juxtamembrane Domainsmentioning

confidence: 99%

Receptor tyrosine kinase transmembrane domains

Hristova

2010

Cell Adhesion & Migration

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“…As measured by 3 Hthymidine incorporation, D816V KIT-transformed Ba/F3 cells were resistant to treatment with imatinib ( Figure 3 19 Previous reports have shown that STAT3 is aberrantly phosphorylated by D816V KIT. 20,21 PCR of the KIT gene Using PCR of KIT exon 17 followed by direct sequencing or sequencing of cloned RT-PCR products, the D816V KIT mutation was detected in the patient's bone marrow at the time of initial presentation in April 2003 and from peripheral blood after completion of 1 cycle of PKC412. However, these methods could not detect the D816V KIT mutation in the bone marrow after 2 cycles of therapy or from peripheral blood obtained at the completion of 3 cycles of PKC412 (during disease progression).…”

Section: In Vitro Analysis Of the Effects Of Pkc412 On D816v Kit-tranmentioning

confidence: 99%

Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation

Gotlib

Berubé

Growney

et al. 2005

Blood

222

193

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“…14,15 They include the classical phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) pathways, as well as a number of signaling proteins activated by many cell-surface receptors such as p38, JNK, VAV, STAT-1, STAT-3, and STAT-5. Activation of PI3K is critical for both WT and mutant KIT in all models studied, while the activation of the mitogen-activated protein (MAP) kinases ERK-1 and ERK-2 appears to be dependent on the cellular context.…”

Section: Introductionmentioning

confidence: 99%

The tyrosine kinase FES is an essential effector of KITD816V proliferation signal

Voisset

Lopez

Dubreuil

et al. 2007

Blood

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KIT is a tyrosine kinase receptor that is aberrantly activated in several neoplasms. In human pathologies, the most frequent mutation of KIT occurs at codon 816. The resulting KIT mutant protein is activated in the absence of ligand and is resistant to the clinically available inhibitors of KIT. In this report, we provide evidence for an essential function of the cytoplasmic tyrosine kinase FES downstream of KIT D816V . FES is phosphorylated on tyrosine residues in cells that carry KIT D816V mutation, and this phosphorylation is KIT dependent. Reduction of FES expression using RNA interference results in decreased cell proliferation in human or murine cells harboring KIT D816V IntroductionThe proto-oncogene c-kit encodes a receptor with tyrosine kinase activity which is essential for hematopoiesis and the development of melanoblasts, germ cells, and interstitial cells of Cajal. Gain-offunction mutations of KIT are implicated in human pathologies. These mutations have been classified as regulatory-type mutations when they affect domains of the receptor necessary for maintaining KIT autoinhibition and structural-type mutations when they directly affect the catalytic domain. Juxtamembrane mutations of KIT are commonly found in gastrointestinal stromal tumors (GISTs), 1 whereas kinase domain mutations are mainly found in mastocytosis, 2 hematologic neoplasms, [3][4][5] and germ-cell tumors. [6][7][8] Very recently, both juxtamembrane and kinase domain mutations of KIT have also been reported in melanomas. 9 The most frequent mutation affects codon 816 in human c-kit cDNA, which corresponds to codon 814 in the homologous mouse sequence. 10 Whereas tyrosine kinase inhibitors such as imatinib are very efficient on wild-type KIT (KIT WT ) and KIT juxtamembrane mutations, KIT D816V is resistant to this treatment. [11][12][13] Therefore, drugs that could target this mutant or an essential downstream effector would be useful tools for the study and the treatment of the associated diseases.Signaling proteins activated downstream of gain-of-function mutants of KIT include many proteins shown previously to participate in wild-type KIT receptor signal transduction. 14,15 They include the classical phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) pathways, as well as a number of signaling proteins activated by many cell-surface receptors such as p38, JNK, VAV, STAT-1, STAT-3, and STAT-5. Activation of PI3K is critical for both WT and mutant KIT in all models studied, while the activation of the mitogen-activated protein (MAP) kinases ERK-1 and ERK-2 appears to be dependent on the cellular context. The importance of each protein or signaling pathway activated downstream of KIT D816V has yet to be fully evaluated.Fps/fes was originally identified as an oncogene from avian (fps) and feline (fes) retroviruses. FES (feline sarcoma) and FER (FES-related) proteins are the only 2 members of a subfamily of cytoplasmic protein tyrosine kinase. 16 FES has been shown to associate with growth factor an...

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Signal transduction by several KIT juxtamembrane domain mutations

Cited by 66 publications

References 49 publications

Receptor tyrosine kinase transmembrane domains

Receptor tyrosine kinase transmembrane domains

Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation

The tyrosine kinase FES is an essential effector of KITD816V proliferation signal

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