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

Blood ◽  
1999 ◽  
Vol 93 (4) ◽  
pp. 1338-1345 ◽  
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.

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

Blood ◽  
1999 ◽  
Vol 93 (4) ◽  
pp. 1338-1345 ◽  
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

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.

Intrinsic Regulation of the Interactions between the SH3 Domain of p85 Subunit of Phosphatidylinositol-3 Kinase and BCR/ABL Oncogenic Tyrosine Kinase.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2961-2961
Author(s):  
Shuyue Ren ◽  
Fan Xue ◽  
Jan Feng ◽  
Tomasz Skorski
Keyword(s):  
Catalytic Activity ◽  
Tyrosine Kinase ◽  
Philadelphia Chromosome ◽  
Sh3 Domain ◽  
Myelogenous Leukemia ◽  
Wild Type ◽  
Phosphatidylinositol 3 Kinase ◽  
Abl Kinase ◽  
Intrinsic Regulation ◽  
Phosphatidylinositol 3

Abstract BCR/ABL fusion tyrosine kinase is responsible for the initiation and maintenance of the Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) and a cohort of acute lymphocytic leukemias (ALL). Our previous studies showed that a signaling protein phosphatidylinositol-3 kinase (PI-3k) is essential for the growth of CML cells, but not of normal hematopoietic cells, and that p85 subunit of PI-3k co-immunoprecipitates with BCR/ABL (Skorski et al., (1995) Blood 86, 726–36; Skorski et al., (1997) Embo J 16, 6151–61; Klejman et al., (2002) Oncogene 21, 5868–76). Therefore, we made an attempt to better characterize the p85 - BCR/ABL interactions. Here we show that SH3 domain of p85 (p85-SH3) pulls-down the p210BCR/ABL kinase from hematopoietic cell lysates. In addition, we characterize the p85-SH3 mutants, which abrogate or enhance this interaction. The results of pull-down assays of the p85-SH3 mutants seem to support the assumption that p85-SH3 interacts with the BCR/ABL protein network via the proline-rich (PxxP) region. One of the surprising findings was the enhanced binding affinity of the tyrosine to phenylalanine p85-SH3 domain mutants in comparison to the wild-type p85-SH3. Based on these results we speculate on the capability of p85-SH3 to interact with BCR/ABL and on the p85-SH3 conformational requirements necessary for this reaction. PxxP - binding appears to be required for the interaction of p85-SH3 with BCR/ABL protein complex and activation of the catalytic activity of PI-3k, whereas subsequent BCR/ABL-dependent phosphorylation of the tyrosines may facilitate the release of activated PI-3k from the complex.

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

1997 ◽  
Vol 94 (18) ◽  
pp. 9687-9692 ◽  
Author(s):  
K. Diener ◽  
X. S. Wang ◽  
C. Chen ◽  
C. F. Meyer ◽  
G. Keesler ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Germinal Center ◽  
Kinase Pathway ◽  
Novel Protein

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

Reproduction ◽  
2000 ◽  
pp. 377-383 ◽  
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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