gative impact on both PI3K activation downstream of Kit and FcεRI, and Gab2-deficient mice have an almost complete block in the allergic response. This reduction is more severe than that observed in p110δ-deficient mice , possibly because Gab2 also binds other class IA PI3Ks, including p110α and ADX-47273 851881-60-2 p110β. We have previously reported that a high dose of IC87114 could completely wipe out the PCA response. We presumed at the time that this was due to possible off-target effects of this compound on p110γ. Our current data show that this is not the case and that other PI3K isoforms, either on their own or in combination, account for the PI3K-dependent fraction of the IgE/Agdependent allergic response. Taken together, it is therefore possible that the p110α and p110β isoforms of PI3K together contribute to the residual PI3K-dependent PCA response observed upon p110δ inactivation.
However, on its own, AR-42 HDAC inhibitor p110β does not significantly contribute to the PCA response. Unfortunately, selectivity of inhibitors for p110α cannot be achieved at present without resulting in many off-target effects, so that the currently available p110α inhibitors also inhibit other relevant kinases including isoforms of protein kinase C. Genetic investigation of the role of p110α PI3K isoforms has thus far also been precluded due to the embryonic lethality of homozygous p110α and p110β gene-targeted mice and the incapacity to derive cell lines from these mice. The creation of mice with conditional p110α and p110β alleles and the development of small molecule inhibitors with higher p110α isoform-selectivity will be critical to gain insight into which other PI3K isoforms may complement p110δ in controlling the IgE/Ag-dependent allergic response.
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