Src homology 2 domain-containing inositol 5-phosphatase 1 mediates cell cycle arrest by FcgammaRIIB.
We previously found that low affinity receptors for the Fc portion of IgG, FcgammaRIIB, 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 FcgammaRIIB, FcgammaRIIB-deficient mast cells reconstituted with wild-type or mutated FcgammaRIIB, and Src homology 2 domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1)-deficient mast cells. We found that, upon coaggregation with Kit, FcgammaRIIB 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. FcgammaRIIB-mediated inhibition of Kit-dependent cell proliferation was reduced in SHIP1-deficient mast cells, whereas inhibition of IgE-induced responses was abrogated. Cell proliferation was, however, inhibited by coaggregating Kit with FcgammaRIIB whose intracytoplasmic domain was replaced with the catalytic domain of SHIP1. These results demonstrate that FcgammaRIIB 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, FcgammaRIIB can use other effectors that specifically inhibit cell proliferation.
Malbec
O
O
Laboratoire d'Immunologie Cellulaire et Clinique, INSERM U.255, Institut Curie, 75005 Paris, France.
Schmitt
C
C
Bruhns
P
P
Krystal
G
G
Fridman
W H
WH
Daëron
M
M
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism*; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D020134:Catalytic Domain; D002453:Cell Cycle; D002455:Cell Division; D002470:Cell Survival; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D020935:MAP Kinase Signaling System; D051379:Mice; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D051381:Rats; D017452:Receptors, IgG / Q000737:chemistry* / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
D015703:Antigens, CD; D018076:DNA, Complementary; C080571:Fc gamma receptor IIB; D017452:Receptors, IgG; D019089:Stem Cell Factor; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D019009:Proto-Oncogene Proteins c-kit; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D013936:Thymidine