Fig. 1. SHIP1 and its role in cancer and mucosal inflammation.

A. SHIP1 is a 1189 amino acid (1188 aa for isoform b) protein consisting of several different domains, namely the central catalytic domain (5’-PPase) flanked by a PH-like (PH-L) and a C2 domain for binding of the substrate PI(3,4,5)P₃ and product PI(3,4)P₂ of the enzyme, respectively. The N-terminal region contains a SH2-domain, while the C-terminal “proline-rich” region contains PXXP motifs for interactions with SH3-containing proteins and two NPXY motifs for interaction with Phospho-Tyrosine Binding (PTB) protein. Phosphorylation of Ser440 by PKA has been shown to increase enzymatic activity and the aspartic acid at position 672 (D672) has been identified as a critical catalytic residue. B. The “two PIP hypothesis” suggests that both the substrate, PI(3,4,5)P₃, and the product,PI(3,4)P₂, of SHIP are necessary to fully activate Akt in order to achieve and maintain the malignant state. As such, selective SHIP1 or pan-SHIP1/2 inhibition can trigger cancer cell death both in vitro and in vivo. C. SHIP may also be involved in regulating Fas trimerization at the cell membrane and would thus serve a protective function against downstream Caspase 8 signaling. Selective SHIP inhibition may therefore have a dual role in triggering apoptosis in cancer cells, via reduced AKT activation and increased Caspase 8 activation. The latter mechanism also suggests that SHIP inhibition may prove useful in reducing inappropriate persistence of autoreactive effector T cells at mucosal surfaces by lifting the inhibition imposed on pathways downstream of Fas.