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 Citations (Scopus)

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

Fingerprint

abl Genes
Heat-Shock Proteins
Protein Kinases
Chemical activation
Myeloid Leukemia
Chromosomes
Cells
Philadelphia Chromosome
germinal center kinases
JNK Mitogen-Activated Protein Kinases
Protein-Serine-Threonine Kinases
Signal Transduction
Catalyst activity
Association reactions
Cell Line

ASJC Scopus subject areas

  • Hematology

Cite this

GCKR links the Bcr-Abl oncogene and Ras to the stress-activated protein kinase pathway. / Shi, Chong Shan; Tuscano, Joseph M.; Witte, Owen N.; Kehrl, John H.

In: Blood, Vol. 93, No. 4, 15.02.1999, p. 1338-1345.

Research output: Contribution to journalArticle

Shi, CS, Tuscano, JM, Witte, ON & Kehrl, JH 1999, 'GCKR links the Bcr-Abl oncogene and Ras to the stress-activated protein kinase pathway', Blood, vol. 93, no. 4, pp. 1338-1345.
Shi, Chong Shan ; Tuscano, Joseph M. ; Witte, Owen N. ; Kehrl, John H. / GCKR links the Bcr-Abl oncogene and Ras to the stress-activated protein kinase pathway. In: Blood. 1999 ; Vol. 93, No. 4. pp. 1338-1345.
@article{0cc73d03551d4a33a625619281c46cfe,
title = "GCKR links the Bcr-Abl oncogene and Ras to the stress-activated protein kinase pathway",
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.",
author = "Shi, {Chong Shan} and Tuscano, {Joseph M.} and Witte, {Owen N.} and Kehrl, {John H.}",
year = "1999",
month = "2",
day = "15",
language = "English (US)",
volume = "93",
pages = "1338--1345",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "4",

}

TY - JOUR

T1 - GCKR links the Bcr-Abl oncogene and Ras to the stress-activated protein kinase pathway

AU - Shi, Chong Shan

AU - Tuscano, Joseph M.

AU - Witte, Owen N.

AU - Kehrl, John H.

PY - 1999/2/15

Y1 - 1999/2/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0033557972&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033557972&partnerID=8YFLogxK

M3 - Article

C2 - 9949177

AN - SCOPUS:0033557972

VL - 93

SP - 1338

EP - 1345

JO - Blood

JF - Blood

SN - 0006-4971

IS - 4

ER -