GCKR links the Bcr-Abl oncogene and Ras to the stress-activated protein kinase pathway

Chong Shan Shi, Joseph M. Tuscano, Owen N. Witte, John H. Kehrl

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

The Bcr-Abl oncogene, found in Philadelphia chromosome-positive myelogenous leukemia (CML), activates Ras and triggers the stress-activated protein kinase (SAPK or Jun NH2-terminal kinase [JNK]) pathway. Interruption of Ras or SAPK activation dramatically reduces Bcr-Abl-mediated transformation. Here, we report that Bcr-Abl through a Ras-dependent pathway signals the serine/threonine protein kinase GCKR (Germinal Center Kinase Related) leading to SAPK activation. Either an oncogenic form of Ras or Bcr- Abl enhances GCKR catalytic activity and its activation of SAPK, whereas inhibition of GCKR impairs Bcr-Abl-induced SAPK activation. Bcr-Abl mutants that are impaired for GCKR activation are also unable to activate SAPK. Consistent with GCKR being a functional target in CML, GCKR is constitutively active in CML cell lines and found in association with Bcr-Abl. Our results indicate that GCKR is a downstream target of Bcr-Abl and strongly implicate GCKR as a mediator of Bcr-Abl in its transformation of cells.

Original languageEnglish (US)
Pages (from-to)1338-1345
Number of pages8
JournalBlood
Volume93
Issue number4
StatePublished - Feb 15 1999

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ASJC Scopus subject areas

  • Hematology

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