Activation of the c-Jun N-terminal kinase pathway by a novel protein kinase related to human germinal center kinase

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.

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GCKR Links the Bcr-Abl Oncogene and Ras to the Stress-Activated Protein Kinase Pathway

Blood ◽

10.1182/blood.v93.4.1338 ◽

1999 ◽

Vol 93 (4) ◽

pp. 1338-1345 ◽

Cited By ~ 24

Author(s):

Chong-Shan Shi ◽

Joseph M. Tuscano ◽

Owen N. Witte ◽

John H. Kehrl

Keyword(s):

Catalytic Activity ◽

Protein Kinase ◽

Germinal Center ◽

Philadelphia Chromosome ◽

Myelogenous Leukemia ◽

Jnk Pathway ◽

Downstream Target ◽

Kinase Pathway ◽

Dependent Pathway ◽

Oncogenic Form

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.

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1333: Proteinase-Activated Receptor-2 Activation of the Mitogen Activated Protein Kinase Pathway in Human Cultured Prostate Stromal Cells

The Journal of Urology ◽

10.1016/s0022-5347(18)38558-6 ◽

2004 ◽

Vol 171 (4S) ◽

pp. 351-351

Author(s):

Andrew Myatt ◽

Duncan R. Harriss ◽

Stephen J. Hill

Keyword(s):

Protein Kinase ◽

Stromal Cells ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Kinase Pathway

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Regulation of spontaneous and induced resumption of meiosis in mouse oocytes by different intracellular pathways

Reproduction ◽

10.1530/reprod/120.2.377 ◽

2000 ◽

pp. 377-383 ◽

Cited By ~ 13

Author(s):

L Leonardsen ◽

A Wiersma ◽

M Baltsen ◽

AG Byskov ◽

CY Andersen

Keyword(s):

Signal Transduction ◽

Protein Kinase ◽

Protein Kinase A ◽

Mitogen Activated Protein Kinase ◽

Meiotic Maturation ◽

Mouse Oocytes ◽

Mitogen Activated Protein ◽

Dependent Signal ◽

Kinase Pathway ◽

Kinase A

The mitogen-activated protein kinase-dependent and the cAMP-protein kinase A-dependent signal transduction pathways were studied in cultured mouse oocytes during induced and spontaneous meiotic maturation. The role of the mitogen-activated protein kinase pathway was assessed using PD98059, which specifically inhibits mitogen-activated protein kinase 1 and 2 (that is, MEK1 and MEK2), which activates mitogen-activated protein kinase. The cAMP-dependent protein kinase was studied by treating oocytes with the protein kinase A inhibitor rp-cAMP. Inhibition of the mitogen-activated protein kinase pathway by PD98059 (25 micromol l(-1)) selectively inhibited the stimulatory effect on meiotic maturation by FSH and meiosis-activating sterol (that is, 4,4-dimethyl-5alpha-cholest-8,14, 24-triene-3beta-ol) in the presence of 4 mmol hypoxanthine l(-1), whereas spontaneous maturation in the absence of hypoxanthine was unaffected. This finding indicates that different signal transduction mechanisms are involved in induced and spontaneous maturation. The protein kinase A inhibitor rp-cAMP induced meiotic maturation in the presence of 4 mmol hypoxanthine l(-1), an effect that was additive to the maturation-promoting effect of FSH and meiosis-activating sterol, indicating that induced maturation also uses the cAMP-protein kinase A-dependent signal transduction pathway. In conclusion, induced and spontaneous maturation of mouse oocytes appear to use different signal transduction pathways.

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