Structure, function, and biology of SHIP proteins

Phosphoinositide-Regulated Kinases and Phosphoinositide Phosphatases

“…Several cellular lipid phosphatases have been identified that will dephosphorylate PtdIns(3,4,5)P 3 to PtdIns(3,4)P 2 in vitro, most of them members of a family of phosphatases that has been termed the inositol polyphosphate 5-phosphatase family. , These include the synaptojanins, , Oculocerebrorenal (Lowe) (OCRL) phosphatase, the type II , and type IV 5-phosphatases, as well as the SH2-containing inositol phosphatase-1 (SHIP1) and SHIP2 . However, thus far evidence is lacking that the synaptojanins, OCRL, the type II, and type IV 5-phosphatases antagonize growth factor-stimulated PI3K signaling, and studies indicate that the principle cellular substrate for some of these phosphatases may be PtdIns(4,5)P 2 rather than PtdIns(3,4,5)P 3 . − , In contrast, there is significant evidence that SHIP1 and SHIP2 function as cellular PtdIns(3,4,5)P 3 phosphatases converting PtdIns(3,4,5)P 3 to another putative second messenger PtdIns(3,4)P 2 .…”

“…Significant research has shown that both SHIP1 and SHIP2 possess SH2 domains and are recruited to growth factor/cytokine receptors following stimulation of cells through the interaction of the SH2 domain with tyrosine-phoshorylated receptors. ,,, There is no evidence that this interaction activates the SHIP phosphatatses but may play an important role in bringing the phosphatases to their physiological PtdIns(3,4,5)P 3 substrate at cell membranes. SHIP1 and SHIP2 also become phosphorylated on tyrosine residues following stimulation; however, this does not appear to affect the enzymic activity of SHIP, and the role that this phosphorylation plays is not clear. ,, While the expression of SHIP1 is largely restricted to haematopoietic cells, SHIP2 appears to be more widely expressed.…”

Identification of a NPXY Motif in Growth Factor Receptor-Bound Protein 14 (Grb14) and Its Interaction with the Phosphotyrosine-Binding (PTB) Domain of IRS-1

“…The NPXY motif was first recognized in low-density lipoprotein receptor-related protein (LRP) and subsequently recognized in numerous other cell surface receptors (24). In addition to cell surface receptors, the NPXY motif is also present in the cytoplasmic protein, SHIP (28). NPXY signals were initially thought to be involved in endocytosis, but recent studies have shown that NPXY motifs are recognized by proteins containing PTB or PID motifs (25).…”

INPP5D limits plaque formation and glial reactivity in the APP/PS1 mouse model of Alzheimer’s disease

“…SHIP1 negatively regulates targets such as immune cell surface receptors by catalyzing the conversion of PtdIns(3,4,5)P3 to PtdIns(3,4) P2. This lipid dephosphorylation reaction prevents receptor activation, thereby mitigating signal transduction through the phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway 10 . In particular, SHIP1 inhibits phagocytic signal transduction by Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Tyrosine kinase Binding Protein (TYROBP, also known as DAP12) 11 .…”