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J. Biol. Chem., Vol. 275, Issue 39, 29960-29967, September 29, 2000

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p135 Src Homology 2 Domain-containing Inositol 5'-Phosphatase (SHIP) Isoform Can Substitute for p145 SHIP in F_cRIIB1-mediated Inhibitory Signaling in B Cells^*

Michael E. March, David M. Lucas^§, M. Javad Aman, and Kodimangalam S. Ravichandran^¶

From the  Beirne B. Carter Center for Immunology Research and the Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908 and ^§ Ohio State University, Department of Internal Medicine, Columbus, Ohio 43210

The inositol 5'-phosphatase, SHIP (also referred to as SHIP-1 or SHIP), is expressed in all cells of the hematopoietic lineage. Depending on the cell type being investigated and the state of differentiation, SHIP isoforms of several different molecular masses (170, 160, 145, 135, 125, and 110 kDa) have been seen in immunoblots. However, the function of the individual isoforms and the effect of expressing multiple isoforms simultaneously are not understood. Some of these SHIP isoforms have recently been characterized at the level of primary sequence. In this report, we investigated the function of the recently characterized 135-kDa SHIP isoform (SHIP), which appears to possess the catalytic domain but lacks some of the protein-protein interaction motifs at the C terminus. By reconstituting SHIP-deficient DT40 B cells with either SHIP or the better-characterized p145 SHIP, we addressed the function of SHIP in the complete absence of SHIP . We observed that SHIP had enzymatic activity comparable with SHIP and that SHIP was able to reconstitute F_cRIIB1-mediated inhibition of B cell receptor-induced signaling events such as calcium flux and Akt and mitogen-activated protein kinase activation. SHIP was readily phosphorylated in response to B cell receptor cross-linking with the inhibitory receptor F_cRIIB1 and SHIP also interacted with the adapter protein Shc. During these studies we also observed that the SHIP or SHIP interaction with Grb2 is not required for F_cRIIB1-mediated inhibition of calcium flux. These data suggest that SHIP, which is normally expressed in B cells along with SHIP, functions comparably with SHIP and that these two isoforms are not likely to be antagonistic in their function in vivo.

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