Cross-talks between c-Kit and PKC isoforms in HMC-1560 and HMC-1560,816 cells. Different role of PKCδ in each cellular line

Abstract

The c-kit inhibitor STI571 represents one of the most important treatments for patients with mastocytosis. However, intracellular pathways modulated by this compound are not completely defined. Here, STI571 effect on Protein Kinase C (PKC) regulation is determined in HMC-1 mast cell lines. STI571 activates PKCδ isoform resulting in HMC-1(560) apoptosis. The apoptosis observed is PKCδ-dependent, since PKCδ-silencing avoids STI571 effect. c-kit inhibition implies nuclear PKCδ translocation characterized by a clear dependence on actin cytoskeleton integrity in HMC-1(560) cell line, but not in HMC-1(560,816). Therefore, PKCδ modulations can lead to a serious decrease in STI571 treatment-effectiveness.

Differential Requirement for irf8 in Formation of Embryonic and Adult Macrophages in Zebrafish

“…At later stages, definitive hematopoiesis moves to the pronephric kidney, which is the site of adult hematopoiesis [ 5 , 6 ]. More is known about the development of hematopoietic stem cells (HSCs) into different myeloid fates in the definitive wave than in the earlier waves of blood formation [ 2 , 3 , 6 , 7 ], although the mechanisms are not fully understood in either the early or late waves.…”

KIT Mutations and Other Genetic Defects in Mastocytosis

“…34 Key downstream signaling pathways aberrantly activated by oncogenic KIT D816V mutant comprise, among others, PI3-kinase/protein kinase B (AKT), 35 signal transducer and activator of transcription-5 (STAT-5), 36 nuclear factor-kappa B (NF-kB), 37 mammalian target of rapamycin complex 2, 38 and rotein kinase C-delta (PKCd). 39 In addition, the abnormal accumulation of neoplastic MC in SM could result from the deregulation of proapoptotic and antiapoptotic pathways. There is evidence of overexpression of the antiapoptotic molecules B-cell leukemia/lymphoma 2 (BCL-2), BCL-xL, and MCL-1 in KIT D816Vpositive neoplastic MC in SM patients.…”

Identification of Biological and Pharmaceutical Mast Cell‐ and Basophil‐Related Targets

“…About 90% of mastocytosis patients present the D816V mutation within the cytoplasmic tail of the receptor tyrosine kinase KIT. It results in constitutional KIT activation leading to the pathologic mast cell proliferation and mediator release [43,44]. TK signalling can be suppressed by tyrosine kinase inhibitors (TKIs) preventing phosphorylation of target proteins.…”