Cooperation between SHP-2, phosphatidyl inositol 3-kinase and phosphoinositol 5-phosphatase in the Fc gamma RIIb mediated B cell regulation.
Co-clustering B cell receptors (BCR) and type II receptors binding the Fc part of IgG (Fc gamma RIIb) inhibits B cell activation and antibody production. Tyrosine phosphorylation of an intracellular motif of Fc gamma RIIb has been shown to be a prerequisite of the inhibition. After being phosphorylated by BCR-activated tyrosine kinases, the immunoreceptor tyrosine-based inhibitory motif (P-ITIM) of Fc gamma RIIb recruits SH2 domain containing protein tyrosine phosphatase(s) (PTPs) and polyphosphoinositol 5-phosphatase (SHIP) to the vicinity of BCR, which in turn dephosphorylate their specific substrates. This leads to the interruption of signal transduction, consequently to the anergy and/or apoptosis of the cell. The downstream signaling pathways affected by Fc gamma RIIb-BCR co-clustering are not clarified yet, neither the substrates of PTPs are known. We have studied the Fc gamma RIIb mediated B cell inhibition on human Burkitt lymphoma cell line (BL41). From the lysates of BL41 cells SHP-2 and phosphatidylinositol 3-kinase (PI3-K), as well as the protein tyrosine kinase (PTK) Lyn bind both to the BCR-co-clustered Fc gamma RIIb and to its P-ITIM peptide. Lyn hyperphosphorylates the P-ITIM associated molecules, including SHIP in the in vitro protein tyrosine kinase activity assay. The P-ITIM-compelled multi-phosphoprotein complex binds to and activates SHP-2, which in turn dephosphorylates SHIP and Shc and probably other substrates. Subcellular localisation of these signaling molecules is regulated by the phosphotyrosine-SH2 domain interactions, thus dephosphorylation may result in the re-direction of Shc and SHIP within the cell, consequently, in the modulation of their activity. Finally, co-clustering Fc gamma RIIb and BCR or Fc gamma RIIb and CD19 on the intact cells inhibited PI3-K activity as detected in the anti-phosphotyrosine (anti-PY) precipitates. The results indicate that SHP-2 bound to and activated by the BCR co-clustered Fc gamma RIIb, may down-regulate PI3-K activity by dephosphorylating a yet unidentified regulatory molecule, which recruits PI3-K to the cell membrane.
Sármay
G
G
Department of Immunology, Loránd Eötvös University, Göd, Hungary. sar7197@mail.iif.hu
Koncz
G
G
Pecht
I
I
Gergely
J
J
D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D001402:B-Lymphocytes / Q000201:enzymology* / Q000502:physiology; D001667:Binding, Competitive / Q000276:immunology; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010748:Phosphopeptides / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism / Q000502:physiology; D017452:Receptors, IgG / Q000378:metabolism / Q000502:physiology*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction / Q000276:immunology
D015703:Antigens, CD; D000072181:Inositol Polyphosphate 5-Phosphatases; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010748:Phosphopeptides; D010744:Phosphoric Monoester Hydrolases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; C080571:Fc gamma receptor IIB; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human