p85β regulatory subunit of class IA PI3 kinase negatively regulates mast cell growth, maturation, and leukemogenesis

We show that loss of p85 alpha inhibits the growth and maturation of mast cells, whereas loss of p85 beta enhances this process. Whereas restoring the expression of p85 alpha in P85 alpha(-/-) cells restores these functions, overexpression of p85 beta has the opposite effect. Consistently, overexpression of p85 beta in WT mast cells represses KIT-induced proliferation and IL-3-mediated maturation by inhibiting the expression of Microphthalmia transcription factor. Because p85 alpha and p85 beta differ in their N-terminal sequences, chimeric proteins consisting of amino or carboxy-terminal of p85 alpha and/or p85 beta do not rescue the growth defects of p85 alpha(-/-) cells, suggesting cooperation between these domains for normal mast cell function. Loss of p85 beta impaired ligand induced KIT receptor internalization and its overexpression enhanced this process, partly because of increased binding of c-Cbl to p85 beta relative to p85 alpha. In vivo, loss of p85 beta resulted in increased mast cells, and bone marrow transplantation of cells overexpressing p85 beta resulted in significant reduction in some tissue mast cells. Overexpression of p85 beta suppressed the growth of oncogenic KIT-expressing cells in vitro and prolonged the survival of leukemic mice in vivo. Thus, p85 alpha and p85 beta differentially regulate SCF and oncogenic KIT-induced signals in myeloid lineage-derived mast cells. (Blood. 2012;119(17):3951-3961)