Program Officer

National Institute of Allergy and Infectious Diseases

DAIT/TIB/Transplantation Basic Science Section

National Institutes of Health (Bethesda, MD)

Inhibition of PI3K-linked receptors by the SHIP1/Dok1 heterodimer

The SH2 domain-containing inositol 5’-phosphatase SHIP1 is an important regulator of signaling by immunoreceptors. SHIP1 is the primary effector of signaling by FcγRIIb, but also plays a crucial role in signaling by the BCR and FcεRI. The phosphatase activity of SHIP1 degrades PtdIns3,4,5-P3 (PIP3), regulating signaling via phosphitidylinositol 3-kinase (PI3K) linked receptors. Signaling via chemokine and BAFF receptors has been shown to be sensitive to PI3K inhibitors, suggesting that SHIP1 could also inhibit signaling via these receptors. Recent findings in our laboratory also demonstrate that ligation of the BCR in immature B cells results in inhibition of signaling via the chemokine receptor CXCR4 as a consequence of SHIP1 activation. Furthermore, we have shown that SHIP1 is chronically activated in anergic B cells and is required for maintenance of the unresponsive phenotype.
Inhibition of CXCR4 by SHIP1 likely requires the translocation of activated SHIP1 from the BCR complex to the chemokine receptor. As SHIP1 lacks a PH domain, we hypothesize that Dok1 targets SHIP1 to sites of PIP3 production. Using chimeric SHIP1/Dok1 complexes, we seek to define the SHIP1 and Dok1 domains required for PIP3 targeting and inhibition of PI3K-linked receptors.
Initial work has demonstrated our ability to stimulate PIP3 production via ligand coated beads and visualize PIP3 at the plasma membrane using the AktPH-eGFP reporter construct. Future work will focus on the role of SHIP1 in signaling through chemokine and BAFF receptors, with significant implications in the maintenance of immune tolerance and responsiveness.

1994-1997 Calypte Biomedical