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Oncogenic tyrosine kinase NPM/ALK induces activation of the MEK/ERK signaling pathway independently of c-Raf.
Oncogene. 2007 Feb 08; 26(6):813-21.O

Abstract

The mechanisms of cell transformation mediated by the highly oncogenic, chimeric NPM/ALK tyrosine kinase remain only partially understood. Here we report that cell lines and native tissues derived from the NPM/ALK-expressing T-cell lymphoma (ALK+ TCL) display phosphorylation of the extracellular signal-regulated protein kinase (ERK) 1/2 complex. Transfection of BaF3 cells with NPM/ALK induces phosphorylation of EKR1/2 and of its direct activator mitogen-induced extracellular kinase (MEK) 1/2. Depletion of NPM/ALK by small interfering RNA (siRNA) or its inhibition by WHI-154 abrogates the MEK1/2 and ERK1/2 phosphorylation. The NPM/ALK-induced MEK/ERK activation is independent of c-Raf as evidenced by the lack of MEK1/2 and ERK1/2 phosphorylation upon c-Raf inactivation by two different inhibitors, RI and ZM336372, and by its siRNA-mediated depletion. In contrast, ERK1/2 activation is strictly MEK1/2 dependent as shown by suppression of the ERK1/2 phosphorylation by the MEK1/2 inhibitor U0126. The U0126-mediated inhibition of ERK1/2 activation impaired proliferation and viability of the ALK+ TCL cells and expression of antiapoptotic factor Bcl-xL and cell cycle-promoting CDK4 and phospho-RB. Finally, siRNA-mediated depletion of both ERK1 and ERK2 inhibited cell proliferation, whereas depletion of ERK 1 (but not ERK2) markedly increased cell apoptosis. These findings identify MEK/ERK as a new signaling pathway activated by NPM/ALK and indicate that the pathway represents a novel therapeutic target in the ALK-induced malignancies.

Authors+Show Affiliations

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16909118

Citation

Marzec, M, et al. "Oncogenic Tyrosine Kinase NPM/ALK Induces Activation of the MEK/ERK Signaling Pathway Independently of C-Raf." Oncogene, vol. 26, no. 6, 2007, pp. 813-21.
Marzec M, Kasprzycka M, Liu X, et al. Oncogenic tyrosine kinase NPM/ALK induces activation of the MEK/ERK signaling pathway independently of c-Raf. Oncogene. 2007;26(6):813-21.
Marzec, M., Kasprzycka, M., Liu, X., Raghunath, P. N., Wlodarski, P., & Wasik, M. A. (2007). Oncogenic tyrosine kinase NPM/ALK induces activation of the MEK/ERK signaling pathway independently of c-Raf. Oncogene, 26(6), 813-21.
Marzec M, et al. Oncogenic Tyrosine Kinase NPM/ALK Induces Activation of the MEK/ERK Signaling Pathway Independently of C-Raf. Oncogene. 2007 Feb 8;26(6):813-21. PubMed PMID: 16909118.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oncogenic tyrosine kinase NPM/ALK induces activation of the MEK/ERK signaling pathway independently of c-Raf. AU - Marzec,M, AU - Kasprzycka,M, AU - Liu,X, AU - Raghunath,P N, AU - Wlodarski,P, AU - Wasik,M A, Y1 - 2006/08/07/ PY - 2006/8/16/pubmed PY - 2007/3/3/medline PY - 2006/8/16/entrez SP - 813 EP - 21 JF - Oncogene JO - Oncogene VL - 26 IS - 6 N2 - The mechanisms of cell transformation mediated by the highly oncogenic, chimeric NPM/ALK tyrosine kinase remain only partially understood. Here we report that cell lines and native tissues derived from the NPM/ALK-expressing T-cell lymphoma (ALK+ TCL) display phosphorylation of the extracellular signal-regulated protein kinase (ERK) 1/2 complex. Transfection of BaF3 cells with NPM/ALK induces phosphorylation of EKR1/2 and of its direct activator mitogen-induced extracellular kinase (MEK) 1/2. Depletion of NPM/ALK by small interfering RNA (siRNA) or its inhibition by WHI-154 abrogates the MEK1/2 and ERK1/2 phosphorylation. The NPM/ALK-induced MEK/ERK activation is independent of c-Raf as evidenced by the lack of MEK1/2 and ERK1/2 phosphorylation upon c-Raf inactivation by two different inhibitors, RI and ZM336372, and by its siRNA-mediated depletion. In contrast, ERK1/2 activation is strictly MEK1/2 dependent as shown by suppression of the ERK1/2 phosphorylation by the MEK1/2 inhibitor U0126. The U0126-mediated inhibition of ERK1/2 activation impaired proliferation and viability of the ALK+ TCL cells and expression of antiapoptotic factor Bcl-xL and cell cycle-promoting CDK4 and phospho-RB. Finally, siRNA-mediated depletion of both ERK1 and ERK2 inhibited cell proliferation, whereas depletion of ERK 1 (but not ERK2) markedly increased cell apoptosis. These findings identify MEK/ERK as a new signaling pathway activated by NPM/ALK and indicate that the pathway represents a novel therapeutic target in the ALK-induced malignancies. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/16909118/Oncogenic_tyrosine_kinase_NPM/ALK_induces_activation_of_the_MEK/ERK_signaling_pathway_independently_of_c_Raf_ L2 - https://doi.org/10.1038/sj.onc.1209843 DB - PRIME DP - Unbound Medicine ER -