PMID- 10194451
OWN - NLM
STAT- MEDLINE
DCOM- 19990503
LR  - 20161124
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 93
IP  - 8
DP  - 1999 Apr 15
TI  - A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase
      (SHIP2) is constitutively tyrosine phosphorylated and associated with src
      homologous and collagen gene (SHC) in chronic myelogenous leukemia progenitor
      cells.
PG  - 2707-20
AB  - Because of the probable causal relationship between constitutive p210(bcr/abl)
      protein tyrosine kinase activity and manifestations of chronic-phase chronic
      myelogenous leukemia (CML; myeloid expansion), a key goal is to identify relevant
      p210 substrates in primary chronic-phase CML hematopoietic progenitor cells. We
      describe here the purification and mass spectrometric identification of a 155-kD 
      tyrosine phosphorylated protein associated with src homologous and collagen gene 
      (SHC) from p210(bcr/abl)-expressing hematopoietic cells as SHIP2, a recently
      reported, unique SH2-domain-containing protein closely related to
      phosphatidylinositol polyphosphate 5-phosphatase SHIP. In addition to an
      N-terminal SH2 domain and a central catalytic region, SHIP2 (like SHIP1)
      possesses both potential PTB(NPXY) and SH3 domain (PXXP) binding motifs. Thus,
      two unique 5-ptases with striking structural homology are coexpressed in
      hematopoietic progenitor cells. Stimulation of human hematopoietic growth factor 
      responsive cell lines with stem cell factor (SCF), interleukin-3 (IL-3), and
      granulocyte-macrophage colony-stimulating factor (GM-CSF) demonstrate the rapid
      tyrosine phosphorylation of SHIP2 and its resulting association with SHC. This
      finding suggests that SHIP2, like that reported for SHIP1 previously, is linked
      to downstream signaling events after activation of hematopoietic growth factor
      receptors. However, using antibodies specific to these two proteins, we
      demonstrate that, whereas SHIP1 and SHIP2 selectively hydrolyze PtdIns(3,4,5)P3
      in vitro, only SHIP1 hydrolyzes soluble Ins(1,3,4,5)P4. Such an enzymatic
      difference raises the possibility that SHIP1 and SHIP2 may serve different
      functions. Preliminary binding studies using lysates from
      p210(bcr/abl)-expressing cells indicate that both Ptyr SHIP2 and Ptyr SHIP1 bind 
      to the PTB domain of SHC but not to its SH2 domain. Interestingly, SHIP2 was
      found to selectively bind to the SH3 domain of ABL, whereas SHIP1 selectively
      binds to the SH3 domain of Src. Furthermore, in contrast to SHIP1, SHIP2 did not 
      bind to either the N-terminal or C-terminal SH3 domains of GRB2. These
      observations suggest (1) that SHIP1 and SHIP2 may have a different hierarchy of
      binding SH3 containing proteins and therefore may modulate different signaling
      pathways and/or localize to different cellular compartments and (2) that they may
      be substrates for tyrosine phosphorylation by different tyrosine kinases. Because
      recent evidence has clearly implicated both PI(3,4, 5)P3 and PI(3,4)P2 in growth 
      factor-mediated signaling, our finding that both SHIP1 and SHIP2 are
      constitutively tyrosine phosphorylated in CML primary hematopoietic progenitor
      cells may thus have important implications in p210(bcr/abl)-mediated myeloid
      expansion.
FAU - Wisniewski, D
AU  - Wisniewski D
AD  - Sloan-Kettering Institute for Cancer Research, Molecular Pharmacology and
      Therapeutics Program and Molecular Biology Program, New York, NY, USA.
FAU - Strife, A
AU  - Strife A
FAU - Swendeman, S
AU  - Swendeman S
FAU - Erdjument-Bromage, H
AU  - Erdjument-Bromage H
FAU - Geromanos, S
AU  - Geromanos S
FAU - Kavanaugh, W M
AU  - Kavanaugh WM
FAU - Tempst, P
AU  - Tempst P
FAU - Clarkson, B
AU  - Clarkson B
LA  - eng
GR  - P01 CA64593/CA/NCI NIH HHS/United States
GR  - P30 CA08748/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Phosphoproteins)
RN  - 21820-51-9 (Phosphotyrosine)
RN  - 9007-34-5 (Collagen)
RN  - EC 2.7.10.2 (Fusion Proteins, bcr-abl)
RN  - EC 3.1.3.- (phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase)
RN  - EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
RN  - EC 3.1.3.86 (INPPL1 protein, human)
RN  - EC 3.1.3.86 (Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases)
SB  - AIM
SB  - IM
MH  - Collagen/*genetics
MH  - Fusion Proteins, bcr-abl/genetics
MH  - Hematopoietic Stem Cells/*metabolism/pathology
MH  - Humans
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology/*genetics/pathology
MH  - Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
MH  - Phosphoproteins/isolation & purification/metabolism
MH  - Phosphoric Monoester Hydrolases/genetics/*metabolism
MH  - Phosphorylation
MH  - Phosphotyrosine/metabolism
MH  - Tumor Cells, Cultured
MH  - *src Homology Domains
EDAT- 1999/04/09 00:00
MHDA- 1999/04/09 00:01
CRDT- 1999/04/09 00:00
PHST- 1999/04/09 00:00 [pubmed]
PHST- 1999/04/09 00:01 [medline]
PHST- 1999/04/09 00:00 [entrez]
PST - ppublish
SO  - Blood. 1999 Apr 15;93(8):2707-20.