| First Author | Ming-Lum A | Year | 2012 |
| Journal | FASEB J | Volume | 26 |
| Issue | 8 | Pages | 3163-77 |
| PubMed ID | 22651931 | Mgi Jnum | J:187445 |
| Mgi Id | MGI:5437147 | Doi | 10.1096/fj.11-201475 |
| Citation | Ming-Lum A, et al. (2012) A pleckstrin homology-related domain in SHIP1 mediates membrane localization during Fcgamma receptor-induced phagocytosis. FASEB J 26(8):3163-77 |
| abstractText | SH2 domain-containing inositol-5'-phosphatase-1 (SHIP1) inhibits inflammation by hydrolyzing phosphoinositide-3'-kinase generated membrane phosphatidylinositol-3,4,5-trisphosphate (PIP(3)). Bioinformatic analysis of SHIP1 from multiple species revealed a pleckstrin homololgy-related (PH-R) domain, which we hypothesize mediates SHIP1's association with the membrane, a requirement for its biological function. Recombinant murine SHIP1 PH-R domain was subjected to biophysical and biochemical analysis. Residues K370 and K397 were found to be important for PH-R domain association with membrane PIP(3). Wild-type PH-R domain bound PIP(3) with 1.9 +/- 0.2 nM affinity, while the affinity of a K370A/K397A substituted mutant was too low to measure. Wild-type (but not the K370A/K397A substituted) full-length SHIP1 protein, reconstitutes normal inhibition of Fcgamma receptor-mediated phagocytosis when introduced into SHIP1(-/-) murine macrophages, reducing the number of phagocytic events by 2-fold as compared to SHIP1(-/-) cells. In fact, the PH-R-mediated membrane interaction appears to be a major mechanism by which SHIP1 is recruited to the membrane, since the K370A/K397A substitution reduced the recruitment of both full-length SHIP1 and the PH-R domain by >/=2-fold. We have previously shown that SHIP1 enzyme activity can be targeted for therapeutic purposes. The current studies suggest that molecules targeting the PH-R domain can also modulate SHIP1 function. |
