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Altered lipid raft composition and defective cell death signal transduction in glycosylphosphatidylinositol anchor‐deficient PIG‐A mutant cells
Author(s) -
Szpurka Hadrian,
Schade Andrew E.,
Jankowska Anna M.,
Maciejewski Jaroslaw P.
Publication year - 2008
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2008.07203.x
Subject(s) - lipid raft , signal transduction , mapk/erk pathway , biology , microbiology and biotechnology , haematopoiesis , somatic cell , p38 mitogen activated protein kinases , k562 cells , kinase , pi3k/akt/mtor pathway , apoptosis , tumor necrosis factor alpha , stem cell , immunology , biochemistry , gene
Summary Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal disorder of haematopoietic stem cells caused by somatic PIGA mutations, resulting in a deficiency in glycosylphosphatidylinositol‐anchored proteins (GPI‐AP). Because GPI‐AP associate with lipid rafts (LR), lack of GPI‐AP on PNH cells may result in alterations in LR‐dependent signalling. Conversely, PNH cells are a suitable model for investigating LR biology. LR from paired, wild‐type GPI(+), and mutant GPI(−) cell lines (K562 and TF1) were isolated and analysed; GPI(−) LR contained important anti‐apoptotic proteins, not found in LR from GPI(+) cells. When methyl‐β‐cyclodextrin (MβCD) was utilized to probe for functional differences between normal and GPI(−) LR, increased levels of phospho‐p38 mitogen‐activated protein kinase (MAPK), and phospho‐p65 nuclear factor NF‐κB were found in control and GPI(−) cells respectively. Subsequent experiments addressing the inhibition of phosphoinositide‐3‐kinase (PI3K) suggest that the PI3K/AKT pathway may be responsible for the resistance of K562 GPI(−)cells to negative effects of MβCD. In addition, transduction of tumour necrosis factor‐α (TNF‐α) signals in a LR‐dependent fashion increased induction of p38 MAPK in GPI(+) and increased pro‐survival NF‐κB levels in K562 GPI(−) cells. Therefore, we suggest that the altered LR‐dependent signalling in PNH‐like cells may induce different responses to pro‐inflammatory cytokines from those observed in cells with intact GPI‐AP.