Dok1 and SHIP act as negative regulators of v-Abl-induced pre-B cell transformation, proliferation and Ras/Erk activation

Shinji Oki, André Limnander, Mei Yao Pin, Masaru Niki, Pier Paolo Pandolfi, Paul B. Rothman

Research output: Contribution to journalArticle

Abstract

The v-Abl tyrosine kinase activates several signaling pathways during transformation of bone marrow cells in mice. Because the SH2-containing inositol 5′-phosphatase (SHIP) and Downstream of tyrosine kinase 1 (Dok1) have been shown to interact with Abl, the effect of SHIP and Dok1 deficiency on v-Abl transformation was investigated. Bone marrow cells from either Dok1- or SHIP-deficient mice are more susceptible to transformation by v-Abl. v-Abl-transformed preB cells from these knockout mice show Abl kinase-dependent hyperproliferation and moderate resistance to apoptosis. Elevated activation of Ras, Raf-1, and Erk, but not of Akt, was observed in either SHIP-/- or Dok1-/- v-Abl-transformed cells. This activation is sensitive to treatment with STI571. Furthermore, treatment of these cells with either a farnesyltransferase inhibitor or a MEK1/2 inhibitor abrogates the increased proliferation of SHIP-/- or Dok1-/- cells in a dose-dependent manner. Complementation of SHIP-/- or Dok1 -/- cells abrogates their hyperproliferation and intracellular Erk activation. These data indicate that both SHIP and Dok1 functionally regulate the activation of Ras-Erk pathway by v-Abl and affect the mitogenic activity of v-Abl transformed bone marrow cells.

Original languageEnglish (US)
Pages (from-to)309-313
Number of pages5
JournalCell Cycle
Volume4
Issue number2
DOIs
StatePublished - Feb 2005
Externally publishedYes

Keywords

  • Dok
  • Erk
  • Leukemia
  • Ras
  • SHIP
  • v-Abl

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Dok1 and SHIP act as negative regulators of v-Abl-induced pre-B cell transformation, proliferation and Ras/Erk activation'. Together they form a unique fingerprint.

Cite this