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