Isoforms of c-KIT differ in activation of signalling pathways and transformation of NIH3T3 fibroblasts

Caruana, Georgina; Cambareri, Antony C.; Ashman, Leonie K.

doi:10.1038/sj.onc.1202939

Cited by 90 publications

(97 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…When possible, integration of the two approaches may even help to rationalize cytogenetic/molecular studies. 2 We agree with Pitiot et al 1 that exon-11 of the NPM1 gene might well be a new hot spot for NPM1 mutations in AML that requires further investigation in large number of AML patients. …”

supporting

confidence: 66%

“…The two isoforms have different biological activities and the GNNKÀ isoform is the main transcript in several human malignant tumours. 2 In this retrospective study, we quantitatively tested the expression of the Kit and KitA isoforms in 63 adult patients affected by AML evaluated at the diagnosis, in order to evaluate a possible prognostic role of these isoforms in terms of complete remission rate, overall survival (OS) and progression-free survival (PFS).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Molecular detection of GNNK− and GNNK+ c-kit isoforms: a new tool for risk stratification in adult acute myeloid leukaemia

et al. 2007

View full text Add to dashboard Cite

NPM mutant in various cells of several myeloid lineages, indicating multilineage involvement. Indeed, B5-fixed/EDTAdecalcified bone marrow trephines represent the most suitable material for immunohistochemical detection of NPM and studies carried out in such pathological samples have proved to be fully predictive of all types of NPM1 mutations. 2 Immunohistochemistry should not be regarded as competing with molecular biology methods. Rather, because of its rapidity and low cost, it might be a valid alternative for centres that are not equipped for molecular studies. When possible, integration of the two approaches may even help to rationalize cytogenetic/molecular studies. 2 We agree with Pitiot et al. 1 that exon-11 of the NPM1 gene might well be a new hot spot for NPM1 mutations in AML that requires further investigation in large number of AML patients.

show abstract

supporting

confidence: 66%

mentioning

confidence: 99%

Molecular detection of GNNK− and GNNK+ c-kit isoforms: a new tool for risk stratification in adult acute myeloid leukaemia

et al. 2007

View full text Add to dashboard Cite

show abstract

“…The two isoforms have different signalling activities, although these appear to be cell-type specific and possibly context dependent. In NIH3T3 cells (which have low levels of GAB2), both isoforms activate PI3K/Akt signalling but the GNNK À variant also strongly activates MAPK signalling in a Src-dependent manner (Caruana et al, 1999;Voytyuk et al, 2003;Young et al, 2007). However, in haematopoietic cells, PI3K activity is at least partly dependent on Src-family kinase mediated phosphorylation of GAB2 and this can lead to isoform-specific c-Kit activation of PI3K signalling (Yu et al, 2006;Sun et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…However, in haematopoietic cells, PI3K activity is at least partly dependent on Src-family kinase mediated phosphorylation of GAB2 and this can lead to isoform-specific c-Kit activation of PI3K signalling (Yu et al, 2006;Sun et al, 2008). In NIH3T3 cells both isoforms promote resistance to anoikis, but GNNK À also strongly promotes loss of contact inhibition and increases tumourigenicity (Caruana et al, 1999). It is unclear at this time, which isoform predominates in mammary epithelial cells or whether the balance of isoforms is different between the subpopulations.…”

Section: Discussionmentioning

confidence: 99%

c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

et al. 2011

View full text Add to dashboard Cite

BRCA1 mutation-associated breast cancer originates in oestrogen receptor-alpha-negative (ER À ) progenitors in the mammary luminal epithelium. These cells also express high levels of the Kit gene and a recent study demonstrated a correlation between Brca1 loss and Kit over-expression in the mammary epithelium. However, the functional significance of c-Kit expression in the mammary gland is unknown. To address this, c-Kit À and c-Kit þ mammary epithelial subsets were isolated by flow cytometry, characterised for expression of lineage-specific cell markers and functionally analysed by in vitro colony forming and in vivo transplantation assays. The results confirm that the majority of luminal ER À progenitors are c-Kit þ , but also that most stem cells and the differentiated cell populations are c-Kit À . A subset of c-Kit þ cells with high proliferative potential was found in the luminal ER þ population, however, suggesting the existence of a distinct luminal ER þ progenitor cell type. Analysis of mouse Brca1 mammary tumours demonstrated that they expressed Kit and its downstream effector Lyn at levels comparable to the most strongly c-Kit þ luminal ER À progenitors. Consistent with c-Kit being a progenitor cell marker, in vitro threedimensional differentiation of c-Kit þ cells resulted in a loss of c-Kit expression, whereas c-Kit over-expression prevented normal differentiation in vivo. Furthermore, c-Kit was a functional marker of proliferative potential, as c-Kit inhibition by short hairpin knockdown prevented normal epithelial growth and caused cells to undergo apoptosis. Therefore, c-Kit defines distinct progenitor populations in the mammary epithelium and is critical for mammary progenitor survival and proliferation. Importantly, c-Kit is only the second mammary epithelial stem/progenitor marker to be shown to have a functional role in the mammary epithelium and the first marker to be shown to be required for progenitor cell function. The c-Kit signalling network has potential as a target for therapy and/or prevention in BRCA1-associated breast cancer.

show abstract

“…A clone (kit-DH2) expressing D816H mutant c-Kit is included as a positive control (Alexander et al, 1991;Caruana et al, 1998). Caruana et al (1998Caruana et al ( , 1999 also demonstrated a notable ligandindependent transformation of NIH3T3 cells that expressed relatively high levels of wild type c-Kit, particular with its GNNK 7 isoform. By transfecting 293 cells with the GNNK 7 isoform of both wild type and D816H mutant c-kit cDNAs, we show that mutant c-kit-transfected cells have consistently lower levels of c-Kit expression compared with that observed from wild type c-kit-transfected cells, most likely due to the di erential rate of the receptor degradation among these cells .…”

Section: Discussionmentioning

confidence: 99%

STAT3 activation is required for Asp816 mutant c-Kit induced tumorigenicity

Ning

McGuinness

et al. 2001

Oncogene

View full text Add to dashboard Cite

Activating mutations of c-kit at codon 816 (Asp 816 ) have been identi®ed in variety of malignancies, including acute myeloid leukemia (AML), mastocytosis and germ cell tumors. The mutant c-Kit receptor confers cytokine independence and induces tumorigenicity. However, the molecular mechanisms, particularly the changes in the signal transduction pathways, responsible for these biological e ects induced by mutant c-Kit are largely unde®ned. Using the human embryonic kidney cell line, 293, we show in the current report that constitutive activation of STAT3 and STAT1 is associated with

show abstract

Isoforms of c-KIT differ in activation of signalling pathways and transformation of NIH3T3 fibroblasts

Cited by 90 publications

References 41 publications

Molecular detection of GNNK− and GNNK+ c-kit isoforms: a new tool for risk stratification in adult acute myeloid leukaemia

Molecular detection of GNNK− and GNNK+ c-kit isoforms: a new tool for risk stratification in adult acute myeloid leukaemia

c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

STAT3 activation is required for Asp816 mutant c-Kit induced tumorigenicity

Contact Info

Product

Resources

About