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)310-314
Number of pages5
JournalCell cycle (Georgetown, Tex.)
Volume4
Issue number2
StatePublished - Feb 2005
Externally publishedYes

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B-Lymphoid Precursor Cells
Inositol
Phosphoric Monoester Hydrolases
Protein-Tyrosine Kinases
Chemical activation
Cells
Cell Proliferation
Bone Marrow Cells
Bone
Farnesyltranstransferase
Inositol Polyphosphate 5-Phosphatases
Knockout Mice
Phosphotransferases
Apoptosis

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Cite this

Dok1 and SHIP act as negative regulators of v-Abl-induced pre-B cell transformation, proliferation and Ras/Erk activation. / Oki, Shinji; Limnander, André; Pin, Mei Yao; Niki, Masaru; Pandolfi, Pier Paolo; Rothman, Paul B.

In: Cell cycle (Georgetown, Tex.), Vol. 4, No. 2, 02.2005, p. 310-314.

Research output: Contribution to journalArticle

Oki, Shinji ; Limnander, André ; Pin, Mei Yao ; Niki, Masaru ; Pandolfi, Pier Paolo ; Rothman, Paul B. / Dok1 and SHIP act as negative regulators of v-Abl-induced pre-B cell transformation, proliferation and Ras/Erk activation. In: Cell cycle (Georgetown, Tex.). 2005 ; Vol. 4, No. 2. pp. 310-314.
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