title: p85β regulatory subunit of class IA PI3 kinase negatively regulates mast cell growth, maturation, and leukemogenesis.
abstract: We show that loss of p85α inhibits the growth and maturation of mast cells, whereas loss of p85β enhances this process. Whereas restoring the expression of p85α in P85α(-/-) cells restores these functions, overexpression of p85β has the opposite effect. Consistently, overexpression of p85β in WT mast cells represses KIT-induced proliferation and IL-3-mediated maturation by inhibiting the expression of Microphthalmia transcription factor. Because p85α and p85β differ in their N-terminal sequences, chimeric proteins consisting of amino or carboxy-terminal of p85α and/or p85β do not rescue the growth defects of p85α(-/-) cells, suggesting cooperation between these domains for normal mast cell function. Loss of p85β impaired ligand induced KIT receptor internalization and its overexpression enhanced this process, partly because of increased binding of c-Cbl to p85β relative to p85α. In vivo, loss of p85β resulted in increased mast cells, and bone marrow transplantation of cells overexpressing p85β resulted in significant reduction in some tissue mast cells. Overexpression of p85β suppressed the growth of oncogenic KIT-expressing cells in vitro and prolonged the survival of leukemic mice in vivo. Thus, p85α and p85β differentially regulate SCF and oncogenic KIT-induced signals in myeloid lineage-derived mast cells.
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Subha
authors.initials: S
authors.lastname: Krishnan
authors.forename: Raghuveer Singh
authors.initials: RS
authors.lastname: Mali
authors.forename: Baskar
authors.initials: B
authors.lastname: Ramdas
authors.forename: Emily
authors.initials: E
authors.lastname: Sims
authors.forename: Peilin
authors.initials: P
authors.lastname: Ma
authors.forename: Joydeep
authors.initials: J
authors.lastname: Ghosh
authors.forename: Veerendra
authors.initials: V
authors.lastname: Munugalavadla
authors.forename: Philip
authors.initials: P
authors.lastname: Hanneman
authors.forename: Joal D
authors.initials: JD
authors.lastname: Beane
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007938:Leukemia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger; D058543:Class Ia Phosphatidylinositol 3-Kinase; D019009:Proto-Oncogene Proteins c-kit