It is now well established that the phosphatidylinositol-3-kinase (PI-3K) pathway plays a central role in regulating many biologic processes. A key second messenger within this pathway is the plasma membrane– associated PI-3,4,5-P3. This phospholipid is present at low levels in resting cells but is rapidly synthesized from PI-4,5-P2 by PI-3K in response to growth factors, cytokines, and chemokines and attracts pleckstrin homology (PH)–containing proteins to the plasma membrane to mediate its effects. To ensure that the activation of this pathway is appropriately repressed/terminated, the tumor supressor PTEN hydrolyzes this phospholipid back to PI-4,5-P2 while the hemopoietic-specific SH2-containing inositol 5-phosphatase (SHIP) and the ubiquitously expressed SHIP2 break it down to PI-3,4-P2. The full-length 145-kd SHIP translocates to the plasma membrane and becomes both tyrosine phosphorylated and associated with the adaptor protein Shc following stimulation. It prevents the overproduction of myeloid progenitors and the activation of mature B cells, platelets, and mast cells.
Tu and colleagues (page 2028) have now identified a 104-kd form of SHIP (s-SHIP, for stem cell SHIP) that, unlike full-length SHIP, is expressed in embryonic and hemopoietic stem cells but not in lineage-committed or mature hemopoietic cells. Interestingly, s-SHIP, which is the murine homolog of the human SIP-110, is generated by transcription from a promoter within the intron between exons 5 and 6 of the SHIP gene. It thus lacks the SH2 domain of full-length SHIP and is not tyrosine phosphorylated nor associated with Shc following stimulation. But it does bind constitutively to Grb2 and may be recruited via Grb2's SH2 domain to the plasma membrane to regulate PIP3 levels and thus the activation of primitive stem cells. It will be interesting to determine what regulates the switch from s-SHIP to full-length SHIP and the ramifications of this switch.
