title: Balanced interactions between Lyn, the p85alpha regulatory subunit of class I(A) phosphatidylinositol-3-kinase, and SHIP are essential for mast cell growth and maturation.
abstract: The growth and maturation of bone marrow-derived mast cells (BMMCs) from precursors are regulated by coordinated signals from multiple cytokine receptors, including KIT. While studies conducted using mutant forms of these receptors lacking the binding sites for Src family kinases (SFKs) and phosphatidylinositol-3-kinase (PI3K) suggest a role for these signaling molecules in regulating growth and survival, how complete loss of these molecules in early BMMC progenitors (MCps) impacts maturation and growth during all phases of mast cell development is not fully understood. We show that the Lyn SFK and the p85α subunit of class I(A) PI3K play opposing roles in regulating the growth and maturation of BMMCs in part by regulating the level of PI3K. Loss of Lyn in BMMCs results in elevated PI3K activity and hyperactivation of AKT, which accelerates the rate of BMMC maturation due in part to impaired binding and phosphorylation of SHIP via Lyn's unique domain. In the absence of Lyn's unique domain, BMMCs behave in a manner similar to that of Lyn- or SHIP-deficient BMMCs. Importantly, loss of p85α in Lyn-deficient BMMCs not only represses the hyperproliferation associated with the loss of Lyn but also represses their accelerated maturation. The accelerated maturation of BMMCs due to loss of Lyn is associated with increased expression of microphthalmia-associated transcription factor (Mitf), which is repressed in MCps deficient in the expression of both Lyn and p85α relative to controls. Our results demonstrate a crucial interplay of Lyn, SHIP, and p85α in regulating the normal growth and maturation of BMMCs, in part by regulating the activation of AKT and the expression of Mitf.
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W. Walnut Street, Indianapolis, IN 46202, USA.
authors.forename: Peilin
authors.initials: P
authors.lastname: Ma
authors.forename: Sasidhar
authors.initials: S
authors.lastname: Vemula
authors.forename: Veerendra
authors.initials: V
authors.lastname: Munugalavadla
authors.forename: Jinbiao
authors.initials: J
authors.lastname: Chen
authors.forename: Emily
authors.initials: E
authors.lastname: Sims
authors.forename: Jovencio
authors.initials: J
authors.lastname: Borneo
authors.forename: Takako
authors.initials: T
authors.lastname: Kondo
authors.forename: Baskar
authors.initials: B
authors.lastname: Ramdas
authors.forename: Raghuveer Singh
authors.initials: RS
authors.lastname: Mali
authors.forename: Shuo
authors.initials: S
authors.lastname: Li
authors.forename: Eri
authors.initials: E
authors.lastname: Hashino
authors.forename: Clifford
authors.initials: C
authors.lastname: Takemoto
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008407:Mast Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019089:Stem Cell Factor / Q000378:metabolism; D014157:Transcription Factors; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D002868:Chromosomal Proteins, Non-Histone; D051739:Microphthalmia-Associated Transcription Factor; D019089:Stem Cell Factor; D014157:Transcription Factors; C535119:ZFP541 protein, mouse; D058543:Class Ia Phosphatidylinositol 3-Kinase; D019009:Proto-Oncogene Proteins c-kit; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases