SHIP MODULATES IMMUNE RECEPTOR RESPONSES BY REGULATING MEMBRANE ASSOCIATION OF BTK

Membrane recruitment of SHIP is responsible for the inhibitory signal generated by Fc gamma RIIB coligation to the BCR. By reducing the leve l of PIP3, SHIP regulates the association of the tyrosine kinase Btk w ith the membrane through PH domain-phosphoinositol lipid interactions. Inhibition of BCR signaling by either Fc gamma RIIB coligation, membr ane expression of SHIP, or inhibition of PI3K, conditions which result in decreased levels of PIP3, is suppressed by the expression of Btk a s a membrane-associated chimera. Conversely, increasing PIP3 levels by deletion of SHIP results in increased Btk association with the membra ne and hyperresponsive BCR signaling. These results suggest a central role for PIP3 in regulating the B cell stimulatory state by modulating Btk localization and thereby calcium fluxes.