Fig. 2

SHIP1 is a phosphatase involved in phosphoinositide signaling. Activation of a receptor tyrosine kinase (RTK) recruits the p85 subunit of phosphotidylinositol-3 kinase (PI3K). PI3K generates PI(3,4,5)P₃ at the plasma membrane by phosphorylating PI(4,5)P₂. SYNJ1 can dephosphorylate PI(4,5)P₂ back into its precursor, PI4P. PI(3,4,5)P₃ can activate Akt, which can activate various downstream targets, one of which is IKKα of the IKK kinase complex. IKKα activation leads to phosphorylation of IkB, followed by the ubiquitin-mediated proteasomal degradation of IkB, which enables the NF-kB complex to translocate to the nucleus. The NF-kB complex can activate the transcription of its numerous target genes, including genes involved in immune response. SHIP1 can negatively regulate PI3K/Akt signaling. SHIP1 binds to PI(3,4,5)P₃ via its PH-L domain and dephosphorylates PI(3,4,5)P₃ via its 5’ phosphatase catalytic domain to generate PI(4,5)P₂. C2 domain of SHIP1 can bind to PI(4,5)P₂, which is thought to allosterically regulate SHIP1’s phosphatase activity. SH2 domain can dock onto phosphorylated tyrosine residues to regulate the activity of receptors containing immunoreceptor tyrosine activating/inhibiting motif (ITAMs/ITIMs). This domain is also important for SHIP1’s localization within the cell. SHIP1 can be phosphorylated at Ser440 within the 5’ phosphatase domain by PKA to increase the phosphatase activity. Phosphorylation of SHIP1 at Tyr1022 within the NPxY motif allows binding with SHIP1’s own SH2 domain, which may mediate its dimerization or oligomerization. ECS, extracellular space; SH2, src homology 2, PH-L, plectrin homology-like. Figure created in BioRender.com [87, 88, 91, 106, 107, 128]