Ma. Osborne et al., THE INOSITOL 5'-PHOSPHATASE SHIP BINDS TO IMMUNORECEPTOR SIGNALING MOTIFS AND RESPONDS TO HIGH-AFFINITY IGE RECEPTOR AGGREGATION, The Journal of biological chemistry, 271(46), 1996, pp. 29271-29278
Immunoreceptors such as the high affinity IgE receptor, Fc epsilon RI,
and T-cell receptor associated proteins share a common motif, the imm
unoreceptor tyrosine-based activation motif (ITAM). We used the yeast
tribrid system to identify downstream effecters of the phosphorylated
Fc epsilon RI ITAM-containing subunits beta and gamma. One novel cDNA
was isolated that encodes a protein that is phosphorylated on tyrosine
, contains a Src-homology 2 (SH2) domain, inositolpolyphosphate 5-phos
phatase activity, three NXXY motifs, several proline-rich regions, and
is called SHIP. Mutation of the conserved tyrosine or leucine residue
s within the Fc epsilon RI beta or ITAMs eliminates SHIP binding and i
ndicates that the SHIP-ITAM interaction is specific. SHIP also binds t
o ITAMs from the CD3 complex and T cell receptor zeta chain in vitro.
SHIP protein possesses both phosphatidylinositol-3,4,5-trisphosphate 5
'-phosphatase and inositol-1,3,4,5-tetrakisphosphate 5'-phosphatase ac
tivity. Phosphorylation of SHIP by a protein-tyrosine kinase, Lck, res
ults in a reduction in enzyme activity. Fc epsilon RI activation induc
es the association of several tyrosine phosphoproteins with SHIP. SHIP
is constitutively tyrosine-phosphorylated and associated with She and
Grb2. These data suggest that SHIP may serve as a multifunctional lin
ker protein in receptor activation.