Blood, 1 October 2001, Vol. 98, No. 7, pp. 2000-2000
Another SHIP on the horizon
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.
Gerald Krystal
Terry Fox Laboratory
