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SH2-containing inositol 5'-phosphatase inhibits transformation of Abelson murine leukemia virus

Shawn P Fessler1, Naomi Rosenberg, Linda B Baughn

  • 1Immunology Graduate Program, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.

Journal of Virology
|June 24, 2011
PubMed

Insights

Abelson murine leukemia virus (Ab-MLV) v-Abl kinase transforms pre-B cells by reducing SH2-containing inositol 5'-phosphatase (SHIP) levels. This reduction, dependent on v-Abl kinase activity and the Abl SH2 domain, is critical for Ab-MLV-induced cell transformation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Virology

Background:

  • Abelson murine leukemia virus (Ab-MLV) encodes v-Abl, a protein tyrosine kinase that drives pre-B cell transformation.
  • Transformation by v-Abl is known to involve the phosphatidylinositol 3-kinase (PI3K) signaling pathway.
  • SH2-containing inositol 5'-phosphatase (SHIP) antagonizes PI3K signaling, suggesting a potential regulatory role in v-Abl-mediated transformation.

Purpose of the Study:

  • To investigate whether v-Abl modulates PI3K signaling through interaction with SHIP.
  • To determine the mechanism by which v-Abl affects SHIP levels and its functional consequence in Ab-MLV transformation.

Main Methods:

  • Western blot analysis to detect SHIP protein levels in v-Abl expressing cells.
  • Kinase activity assays and domain-specific mutagenesis to assess the role of v-Abl kinase activity and the Abl SH2 domain.
  • Forced expression of SHIP in Ab-MLV-transformed pre-B cells to evaluate its impact on transformation.

Main Results:

  • v-Abl expression leads to a reduction in full-length p145 SHIP protein levels.
  • This reduction is dependent on v-Abl kinase activity and requires signaling through the Abl SH2 domain.
  • Overexpression of SHIP significantly inhibits Ab-MLV pre-B-cell transformation.

Conclusions:

  • v-Abl protein tyrosine kinase reduces SHIP protein levels in a kinase activity-dependent manner.
  • The reduction of SHIP by v-Abl is a critical mechanism contributing to Ab-MLV-induced pre-B-cell transformation.
  • Targeting SHIP levels represents a potential therapeutic strategy for Ab-MLV-related malignancies.

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