Dataset Information

Proteomic and phosphoproteomic profiling of D816V- and V560G-mutant KIT cells

ABSTRACT: The CD117 mast/stem cell growth factor receptor tyrosine kinase (KIT) is critical for haematopoiesis, melanogenesis, and stem cell maintenance. KIT is commonly activated by mutation in cancers including acute myeloid leukaemia, melanoma, and gastrointestinal stromal tumours (GISTs). The kinase and the juxtamembrane domains of KIT are mutation hotspots; with the kinase domain mutation D816V common in leukaemia, and the juxtamembrane domain mutation V560G common in GISTs. Given the importance of mutant KIT signalling in cancer, we have conducted a proteomic and phosphoproteomic analysis of D816V- and V560G-KIT mutations, using an FDCP1 isogenic cell line model.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Cell, Blood

DISEASE(S): Acute Leukemia

SUBMITTER: Nicole Verrills

LAB HEAD: Nikki Verrills

PROVIDER: PXD043783 | Pride | 2025-06-19

REPOSITORIES: Pride

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Publications

Pharmaco-phosphoproteomic analysis of cancer-associated KIT mutations D816V and V560G.

Murray Heather C HC Miller Kasey K Dun Matthew D MD Verrills Nicole M NM

Proteomics 20240209 9

The CD117 mast/stem cell growth factor receptor tyrosine kinase (KIT) is critical for haematopoiesis, melanogenesis and stem cell maintenance. KIT is commonly activated by mutation in cancers including acute myeloid leukaemia, melanoma and gastrointestinal stromal tumours (GISTs). The kinase and the juxtamembrane domains of KIT are mutation hotspots; with the kinase domain mutation D816V common in leukaemia and the juxtamembrane domain mutation V560G common in GISTs. Given the importance of muta ...[more]

PMID: 38334196

Similar Datasets

Project description:Canine mast cell tumour proliferation depends to a large extent on the activity of KIT, a tyrosine kinase receptor. Inhibitors of the KIT tyrosine kinase have recently been introduced and successfully applied as a therapeutic agent for this tumour type. However, little is known on the downstream target genes of this signalling pathway and molecular changes after inhibition. Transcriptome analysis of the canine mast cell tumour cell line C2 treated for up to 72 hours with the tyrosine kinase inhibitor masitinib identified significant changes in the expression levels of approximately 3500 genes representing 16% of the canine genome. Approximately 40% of these genes had increased mRNA expression levels including genes associated with the pro-proliferative pathways of B- and T-cell receptors, chemokine receptors, steroid hormone receptors and EPO-, RAS and MAP kinase signalling. Proteome analysis of C2 cells treated for 72 hours identified 24 proteins with changed expression levels, most of which being involved in gene transcription, e.g. EIA3, EIA4, TARDBP, protein folding, e.g. HSP90, UCHL3, PDIA3 and protection from oxidative stress, GSTT3, SELENBP1. Transcriptome and proteome analysis of neoplastic canine mast cells treated with masitinib confirmed the strong important and complex role of KIT in these cells. Approximately 16% of the total canine genome and thus the majority of the active genes were significantly transcriptionally regulated. Most of these changes were associated with reduced proliferation and metabolism of treated cells. Interestingly, several pro-proliferative pathways were up-regulated which may represent attempts of masitinib treated cells to activate alternative pro-proliferative pathways. These pathways may contain hypothetical targets for a combination therapy with masitinib to further improve its therapeutic effect. The present study aimed at identifying the transcriptional and translational responses of neoplastic canine mast cells to the tyrosine kinase inhibitor masitinib. To this end, C2 cells, a cell line with a tandem duplication in the juxtamembrane unit and thus constitutively activated KIT, were treated with masitinib and changes in the global mRNA and protein expression levels were characterized.

			Action	DRS
	FDCP1_Proteome.mzML	Mzml
	FDCP1_Proteome.mzid.gz	Mzid
	FDCP1_Proteome.pdResult	Other
	FD_NM_D816V_R1_.raw	Raw
	FD_NM_D816V_R2_.raw	Raw