s-SHIP associates with receptor complexes essential for pluripotent stem cell growth and survival.

Embryonic stem (ES) cells are pluripotent cells that have the ability to either self-renew or differentiate into any cell type found in the mammalian body. The signaling pathways required for self-renewal of these cells are yet to be defined. Previously we identified a stem cell-specific isoform of the protein SH2 domain-containing 5'-inositol phosphatase (SHIP) that we call s-SHIP, which is expressed in both pluripotent ES cells and adult tissue-specific multipotent cells, such as hematopoietic stem cells (HSCs). s-SHIP lacks an SH2 domain but contains a 5'-inositol phosphatase domain and several protein-protein interaction domains that potentially enable its participation in many different signaling pathways. Here we show that s-SHIP associates with gp130, which forms a heterodimeric complex with the leukemia inhibitory factor receptor (LIFR). Signaling through LIFR and other receptors that heterodimerize with gp130 is critical for growth and survival of ES cells and HSCs. Our findings provide biochemical evidence that s-SHIP participates in signaling pathways important for the maintenance of pluripotent stem cell populations.