Disease relevance of Pla2g2a

• These results unexpectedly show that there was no apparent inhibitory effect of the SWR-derived (Pla2g2a wild-type) tissue on adenoma formation in the C57BL/6J-Apc(min/+) epithelium [1].
• Aggregation chimeras were formed between C57BL/6 mice heterozygous for the Apc(min) (Min) mutation and wild-type SWR mice, that differ in their Pla2g2a status, a modifier of Apc(min), and also in their resistance to intestinal polyp formation [1].
• Mom1 is a semidominant modifier of polyp size and multiplicity in Min mice (Gould and Dove 1997), and encodes the secretory type II nonpancreatic phospholipase A2 (Pla2g2a) gene (MacPhee et al. 1995; Cornier et al. 1997, 2000) [2].
• Mom1 showed no influence on the development of desmoid fibromas, whereas the combination of piroxicam and difluoromethylornithine exerted a moderate effect [3].
• Because sPLA2 has been identified recently as the MOM1 (modifier of MIN) locus that influences polyp formation in the colon, these studies suggest that sPLA2 may also influence the gastric epithelial response to Helicobacter infection [4].

Psychiatry related information on Pla2g2a

• Pla2g2a is expressed in a variety of cell types and seems to be involved in inflammatory responses and bacterial defense mechanisms [5].
• However, it is not clear whether 14-3-3 indicates general neuronal damage or is of pathophysiological relevance in CJD [6].

High impact information on Pla2g2a

• We previously mapped a strong modifier locus, Mom1 (modifier of Min-1), to a 4-cM region on mouse chromosome 4 containing a candidate gene Pla2g2a encoding a secretory phospholipase [7].
• Here, we report that a cosmid transgene overexpressing Pla2g2a caused a reduction in tumour multiplicity and size, comparable to that conferred by a single copy of the resistance allele of Mom1 [7].
• The association of Pla2g2a with Mom1 thus withstands a strong functional test and is likely to represent the successful identification of a polymorphic quantitative trait locus in mammals [7].
• Using a panel of phosphorylated peptides based on Raf-1, we have defined the 14-3-3 binding motif and show that most of the known 14-3-3 binding proteins contain the motif [8].
• The highly conserved and ubiquitously expressed 14-3-3 family of proteins bind to a variety of proteins involved in signal transduction and cell cycle regulation [8].

Chemical compound and disease context of Pla2g2a

• A large body of research has putatively demonstrated that the Group IIA sPLA2 is involved in diverse pathologic processes, such as rheumatoid arthritis, septic shock, intestinal neoplasia, and epidermal hyperplasia, as well as in cellular signaling by regulating the formation of arachidonate-derived lipid messengers [9].
• We previously demonstrated that secretory phospholipase A2 (sPLA2) and lysophosphatidylcholine (LPC) exhibit neurotrophin-like neuritogenic activity in the rat pheochromocytoma cell line PC12 [10].
• We have found that the expression of five 14-3-3 protein isoforms is induced during the retinoic acid (RA)-mediated differentiation of mouse embryonal carcinoma F9 cells [11].
• This study documents for the first time that psychosine-induced cell death is mediated via the sPLA2 signaling pathway and that inhibitors of sPLA2 may hold a therapeutic potential for protection against oligodendrocyte cell death and resulting demyelination in Krabbe disease [12].
• The acute-phase response was induced in apoA-I/sPLA2 double-transgenic and apoA-I single-transgenic mice by intraperitoneal lipopolysaccharide (LPS) injection [13].

Biological context of Pla2g2a

• One marker mapping distal to Pla2g2a showed LOH in a small minority of spontaneous tumors [14].
• These results establish a novel paradigm for the promotion of nuclear import by 14-3-3 binding [15].
• 14-3-3 proteins are phosphoserine/threonine-binding proteins that play important roles in many regulatory processes, including intracellular protein targeting [15].
• Analysis of chimeric Min mice indicates that the actions of both Apc and Mom1 are localized within the cell lineage that gives rise to intestinal tumors [16].
• Pancreatic secretory PLA2 (sPLA2), via its receptor (sPLA2R), transcriptionally activates COX-2 gene expression in several cell types, although a specific transcription factor mediating COX-2 expression has not yet been identified [17].

Anatomical context of Pla2g2a

• Moreover, the tumor resistance in the colon of Pla2g2aAKR animals is dosage-dependent, a finding that is consistent with our observation that Pla2g2a is expressed in goblet cells [18].
• The current study examined the signal transduction steps involved in the selective release of arachidonic acid (AA) induced by the addition of secretory phospholipase A2 (sPLA2) isotypes to bone marrow-derived mast cells (BMMC) [19].
• This approach enables further studies of the mechanisms of sPLA2 action influencing the development and tumorigenesis of the small intestine and colon in both mice and humans [20].
• Secretory phospholipase A2 (sPLA2) is the major effector involved in arachidonic acid (AA) mobilization and prostaglandin E2 (PGE2) production during stimulation of P388D1 macrophages with the inflammatory stimuli bacterial lipopolysaccharide and platelet-activating factor [21].
• We used the MC3T3-E1 cell line, which originates from C57BL/6J mouse that is genetically type IIA secretory phospholipase A2 (sPLA2)-deficient, to reveal the type IIA sPLA2-independent route of the prostanglandin (PG) biosynthetic pathway [22].

Associations of Pla2g2a with chemical compounds

• Heparin, a cell-impermeable complex carbohydrate with high affinity for Group V PLA2, blocks that association, suggesting that the granules are formed by internalization of the Group V sPLA2 previously associated with the outer cellular surface [23].
• Overexpression of sPLA2 receptors caused a marked increase in AA and PGD2 release after stimulation of BMMC, implicating sPLA2 receptors in this process [19].
• BMMC were also found to express type IIC PLA2 (PLA2-IIC), a recently described novel sPLA2 possessing 16 cysteine residues, expression of which changed minimally after BMMC activation [24].
• Expression of either group IIa PLA2 or V PLA2 enhanced AA release in MC+/+ but had no effect on AA release in MC-/-. When sPLA2 and cPLA2alpha are both present, the effect of H2O2 is manifested by preferential release of AA compared with oleic acid [25].
• Here we show that 14-3-3 is a specific phosphoserine-binding protein [8].

Physical interactions of Pla2g2a

• Promotion of importin alpha-mediated nuclear import by the phosphorylation-dependent binding of cargo protein to 14-3-3 [15].
• A central goal for the near future is to identify the Mom1 gene product and to identify other loci that can interact with the Min mutation and affect tumour multiplicity or progression [26].
• We conclude that 14-3-3 is a latent co-activator bound to unactivated Raf-1 in quiescent cells and mediates mitogen-triggered but Ras-independent regulatory effects aimed directly at the kinase domain [27].
• In summary, we provide convincing evidence that phosphorylation of TG2 by PKA creates binding site(s) for 14-3-3 both in vitro and in vivo [28].
• Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL [29].

Enzymatic interactions of Pla2g2a

• Upon activation of PKA, Raf-1 is phosphorylated and 14-3-3 binds, blocking Raf-1 recruitment to the plasma membrane and preventing its activation [30].
• Oxidative stress and the redox state are also implicated in the survival signaling pathway that involves phosphatidylinositol 3-kinase (PI3-K)/Akt and downstream signaling molecular bindings like Bad/Bcl-X(L) and phosphorylated Bad/14-3-3 [31].

Co-localisations of Pla2g2a

• alpha-Synuclein is colocalized with 14-3-3 and synphilin-1 in A53T transgenic mice [32].

Regulatory relationships of Pla2g2a

• Addition of partially purified sPLA2 from BMMC enhanced cPLA2 activity and AA release [19].
• Delayed PGD2 generation was suppressed by approximately 80% by an antibody raised against recombinant murine type II sPLA2 [24].
• 14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax [33].
• Mouse chimaeras will permit an analysis of the clonality and cell autonomy of Min induced neoplasms and also of the action of Mom1 [26].
• 14-3-3 zeta negatively regulates raf-1 activity by interactions with the Raf-1 cysteine-rich domain [34].

Other interactions of Pla2g2a

• Here, we investigate the range of action of Apc and Mom1 [16].
• Notably, disruption of the mouse group IIA secretory phospholipase A(2) locus (Pla2g2a), a potential source of AA for COX-2, increases tumor number despite the fact that the mutation has been predicted to decrease PG production [35].
• The genetic modifier Mom1 and the pharmacological agents piroxicam and difluoromethylornithine each reduced intestinal adenoma multiplicity in the absence of p53 function [3].
• The effects of the Mom2 locus on reducing polyp multiplicity are stronger than the effects of the Mom1 locus, in both the small and large intestines [2].
• These data suggest that sPLA2 mediate the selective release of AA by binding to cell surface receptors and then inducing signal transduction events that lead to cPLA2 activation [19].

Analytical, diagnostic and therapeutic context of Pla2g2a

• The authors also discuss the further testing of one candidate, the phospholipase gene Pla2g2a, by transgenesis [36].
• Here, we determine whether Min and Mom1 act in a tissue-autonomous fashion using ectopic intestinal isografts [5].
• The significance of these interactions under physiological conditions was demonstrated by co-immunoprecipitation of Raf-1 and 14-3-3 from extracts of quiescent, but not mitogen-stimulated, NIH 3T3 cells [27].
• In contrast, Group IIA sPLA2 message was undetectable as analyzed by Northern blot and reverse transcriptase-polymerase chain reaction [9].
• This identified 170 unique 14-3-3-associated proteins, which show only modest overlap with previous 14-3-3 binding partners isolated by affinity chromatography [37].

References