SHIP1

SHIP1, or SH2-containing inositol-5'-phosphatase 1, is a cytoplasmic enzyme encoded by the INPPL1 gene. It belongs to the inositol phosphatase family and acts as a negative regulator of phosphoinositide 3-kinase (PI3K) signaling by hydrolyzing phosphatidylinositol 3,4,5-trisphosphate (PIP3) to generate PI(3,4)P2 at the plasma membrane. This activity attenuates PI3K/AKT pathway signaling, thereby influencing various cellular responses.

The protein features an N-terminal SH2 domain that mediates recruitment to phosphorylated receptors and adaptor proteins, a central catalytic inositol phosphatase domain, and a C-terminal proline-rich region that supports protein–protein interactions. This domain organization enables SHIP1 to be mobilized to signaling complexes in response to immune receptor engagement and other tyrosine phosphorylation events.

Expression of SHIP1 is highest in hematopoietic cells, including B cells, T cells, and myeloid lineages, where it localizes to the cytoplasm and can associate with membranes upon cellular activation. Functionally, SHIP1 modulates signaling downstream of a range of receptors, such as B cell receptor, T cell receptor, cytokine receptors, and Fc receptors. By reducing PIP3 availability, SHIP1 dampens PI3K-dependent processes like survival, proliferation, and metabolic activity, while the generation of PI(3,4)P2 can elicit distinct signaling outputs depending on cellular context.

Regulation of SHIP1 involves recruitment to signaling complexes through SH2-domain interactions with phosphorylated motifs and control by phosphorylation and adaptor proteins, including DOK family members. Clinically, SHIP1 dysregulation has been associated with immune disorders, hematologic malignancies, and inflammatory diseases. Mouse models lacking SHIP1 show heightened PI3K signaling and altered immune cell function, underscoring SHIP1’s role in maintaining immune homeostasis. Research into pharmacological modulation of SHIP1 continues for potential therapeutic applications in autoimmunity and cancer.