Src Homology 2 Domain-containing Inositol 5-Phosphatase 1 Mediates Cell Cycle Arrest by FcγRIIB

Odile Malbec, Christian Schmitt, Pierre Bruhns, Gerald Krystal, Wolf H. Fridman, Marc Daëron
2001 Journal of Biological Chemistry  
We previously found that low affinity receptors for the Fc portion of IgG, Fc␥RIIB, which are widely expressed by hematopoietic cells, can negatively regulate receptor tyrosine kinase-dependent cell proliferation. We investigated here the mechanisms of this inhibition. We used as experimental models wild-type mast cells, which constitutively express the stem cell factor receptor Kit and Fc␥RIIB, Fc␥RIIB-deficient mast cells reconstituted with wild-type or mutated Fc␥RIIB, and Src homology 2
more » ... Src homology 2 domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1)deficient mast cells. We found that, upon coaggregation with Kit, Fc␥RIIB are tyrosyl-phosphorylated, recruit SHIP1, but not SHIP2, SH2 domain-containing protein tyrosine phosphatase-1 or -2, abrogate Akt phosphorylation, shorten the duration of the activation of mitogen-activated protein kinases of the Ras and Rac pathways, abrogate cyclin induction, prevent cells from entering the cell cycle, and block thymidine incorporation. Fc␥RIIB-mediated inhibition of Kit-dependent cell proliferation was reduced in SHIP1-deficient mast cells, whereas inhibition of IgEinduced responses was abrogated. Cell proliferation was, however, inhibited by coaggregating Kit with Fc␥RIIB whose intracytoplasmic domain was replaced with the catalytic domain of SHIP1. These results demonstrate that Fc␥RIIB use SHIP1 to inhibit pathways shared by receptor tyrosine kinases and immunoreceptors to trigger cell proliferation and cell activation, respectively, but that, in the absence of SHIP1, Fc␥RIIB can use other effectors that specifically inhibit cell proliferation.
doi:10.1074/jbc.m011094200 pmid:11359765 fatcat:ke42wjx43jaz7dbmfpqme3gg4q