SHIP's C-terminus is essential for its hydrolysis of PIP3 and inhibition of mast cell degranulation
| Autor: | Mark D. Ware, Jacqueline E. Damen, Gerald Krystal, Michael R. Hughes, Janet Kalesnikoff |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
MAPK/ERK pathway
animal diseases Immunology Mutant Amino Acid Motifs Blotting Western Genetic Vectors Stem cell factor Bone Marrow Cells Biology Biochemistry Cell Degranulation chemistry.chemical_compound Mice Phosphatidylinositol Phosphates Transduction Genetic medicine Animals Phosphatidylinositol Mast Cells Phosphorylation Protein kinase A Mice Knockout Stem Cell Factor Hydrolysis technology industry and agriculture Degranulation food and beverages Cell Biology Hematology Mast cell Phosphoric Monoester Hydrolases Cell biology medicine.anatomical_structure chemistry Phosphatidylinositol-3 4 5-Trisphosphate 5-Phosphatases Mutagenesis Site-Directed Calcium |
| Zdroj: | Blood. 97(5) |
| ISSN: | 0006-4971 |
| Popis: | The SH2-containing inositol-5'-phosphatase, SHIP, restrains bone marrow-derived mast cell (BMMC) degranulation, at least in part, by hydrolyzing phosphatidylinositol (PI)-3-kinase generated PI-3,4,5-P(3) (PIP3) to PI-3,4-P(2). To determine which domains within SHIP influence its ability to hydrolyze PIP3, bone marrow from SHIP(-/-) mice was retrovirally infected with various SHIP constructs. Introduction of wild-type SHIP into SHIP(-/-) BMMCs reverted the Steel factor (SF)-induced increases in PIP3, calcium entry, and degranulation to those observed in SHIP(+/+) BMMCs. A 5'-phosphatase dead SHIP, however, could not revert the SHIP(-/-) response, whereas a SHIP mutant in which the 2 NPXY motifs were converted to NPXFs (2NPXF) could partially revert the SHIP(-/-) response. SF stimulation of BMMCs expressing the 2NPXF, which could not bind Shc, led to the same level of mitogen-activated protein kinase (MAPK) phosphorylation as that seen in BMMCs expressing the other constructs. Surprisingly, C-terminally truncated forms of SHIP, lacking different amounts of the proline rich C-terminus, could not revert the SHIP(-/-) response at all. These results suggest that the C-terminus plays a critical role in enabling SHIP to hydrolyze PIP(3) and inhibit BMMC degranulation. |
| Databáze: | OpenAIRE |
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