Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway.

Research output: Contribution to journal › Journal article › Research › peer-review

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Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway. / Marzec, M.; Kasprzycka, M.; Liu, X.; El-Salem, M.; Halasa, K.; Raghunath, P. N.; Bucki, R.; Wlodarski, P.; Wasik, M. A.

In: Oncogene, Vol. 26, No. 38, 2007, p. 5606-5614.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Marzec, M, Kasprzycka, M, Liu, X, El-Salem, M, Halasa, K, Raghunath, PN, Bucki, R, Wlodarski, P & Wasik, MA 2007, 'Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway.', Oncogene, vol. 26, no. 38, pp. 5606-5614. https://doi.org/10.1038/sj.onc.1210346

APA

Marzec, M., Kasprzycka, M., Liu, X., El-Salem, M., Halasa, K., Raghunath, P. N., Bucki, R., Wlodarski, P., & Wasik, M. A. (2007). Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway. Oncogene, 26(38), 5606-5614. https://doi.org/10.1038/sj.onc.1210346

Vancouver

Marzec M, Kasprzycka M, Liu X, El-Salem M, Halasa K, Raghunath PN et al. Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway. Oncogene. 2007;26(38):5606-5614. https://doi.org/10.1038/sj.onc.1210346

Author

Marzec, M. ; Kasprzycka, M. ; Liu, X. ; El-Salem, M. ; Halasa, K. ; Raghunath, P. N. ; Bucki, R. ; Wlodarski, P. ; Wasik, M. A. / Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway. In: Oncogene. 2007 ; Vol. 26, No. 38. pp. 5606-5614.

Bibtex

@article{44fd9a76a34847deb159d446f648060e,

title = "Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway.",

abstract = "The mechanisms of cell transformation mediated by the nucleophosmin (NPM)/anaplastic lymphoma kinase (ALK) tyrosine kinase are only partially understood. Here, we report that cell lines and native tissues derived from the NPM/ALK-expressing T-cell lymphoma display persistent activation of mammalian target of rapamycin (mTOR) as detd. by phosphorylation of mTOR targets S6rp and 4E-binding protein 1 (4E-BP1). The mTOR activation is serum growth factor-independent but nutrient-dependent. It is also dependent on the expression and enzymic activity of NPM/ALK as demonstrated by cell transfection with wild-type and functionally deficient NPM/ALK, small interfering RNA (siRNA)-mediated NPM/ALK depletion and kinase activity suppression using the inhibitor WHI-P154. The NPM/ALK-induced mTOR activation is transduced through the mitogen-induced extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway and, to a much lesser degree, through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. Accordingly, whereas the low-dose PI3K inhibitor wortmannin and Akt inhibitor III profoundly inhibited Akt phosphorylation, they had a very modest effect on S6rp and 4E-BP1 phosphorylation. In turn, MEK inhibitors U0126 and PD98059 and siRNA-mediated depletion of either ERK1 or ERK2 inhibited S6rp phosphorylation much more effectively. Finally, the mTOR inhibitor rapamycin markedly decreased proliferation and increased the apoptotic rate of ALK+TCL cells. These findings identify mTOR as a novel key target of NPM/ALK and suggest that mTOR inhibitors may prove effective in therapy of ALK-induced malignancies. [on SciFinder(R)]",

keywords = "tyrosine kinase NPM ALK mTOR signaling pathway cancer",

author = "M. Marzec and M. Kasprzycka and X. Liu and M. El-Salem and K. Halasa and Raghunath, {P. N.} and R. Bucki and P. Wlodarski and Wasik, {M. A.}",

year = "2007",

doi = "10.1038/sj.onc.1210346",

language = "English",

volume = "26",

pages = "5606--5614",

journal = "Oncogene",

issn = "0950-9232",

publisher = "nature publishing group",

number = "38",

}

RIS

TY - JOUR

T1 - Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway.

AU - Marzec, M.

AU - Kasprzycka, M.

AU - Liu, X.

AU - El-Salem, M.

AU - Halasa, K.

AU - Raghunath, P. N.

AU - Bucki, R.

AU - Wlodarski, P.

AU - Wasik, M. A.

PY - 2007

Y1 - 2007

N2 - The mechanisms of cell transformation mediated by the nucleophosmin (NPM)/anaplastic lymphoma kinase (ALK) tyrosine kinase are only partially understood. Here, we report that cell lines and native tissues derived from the NPM/ALK-expressing T-cell lymphoma display persistent activation of mammalian target of rapamycin (mTOR) as detd. by phosphorylation of mTOR targets S6rp and 4E-binding protein 1 (4E-BP1). The mTOR activation is serum growth factor-independent but nutrient-dependent. It is also dependent on the expression and enzymic activity of NPM/ALK as demonstrated by cell transfection with wild-type and functionally deficient NPM/ALK, small interfering RNA (siRNA)-mediated NPM/ALK depletion and kinase activity suppression using the inhibitor WHI-P154. The NPM/ALK-induced mTOR activation is transduced through the mitogen-induced extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway and, to a much lesser degree, through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. Accordingly, whereas the low-dose PI3K inhibitor wortmannin and Akt inhibitor III profoundly inhibited Akt phosphorylation, they had a very modest effect on S6rp and 4E-BP1 phosphorylation. In turn, MEK inhibitors U0126 and PD98059 and siRNA-mediated depletion of either ERK1 or ERK2 inhibited S6rp phosphorylation much more effectively. Finally, the mTOR inhibitor rapamycin markedly decreased proliferation and increased the apoptotic rate of ALK+TCL cells. These findings identify mTOR as a novel key target of NPM/ALK and suggest that mTOR inhibitors may prove effective in therapy of ALK-induced malignancies. [on SciFinder(R)]

AB - The mechanisms of cell transformation mediated by the nucleophosmin (NPM)/anaplastic lymphoma kinase (ALK) tyrosine kinase are only partially understood. Here, we report that cell lines and native tissues derived from the NPM/ALK-expressing T-cell lymphoma display persistent activation of mammalian target of rapamycin (mTOR) as detd. by phosphorylation of mTOR targets S6rp and 4E-binding protein 1 (4E-BP1). The mTOR activation is serum growth factor-independent but nutrient-dependent. It is also dependent on the expression and enzymic activity of NPM/ALK as demonstrated by cell transfection with wild-type and functionally deficient NPM/ALK, small interfering RNA (siRNA)-mediated NPM/ALK depletion and kinase activity suppression using the inhibitor WHI-P154. The NPM/ALK-induced mTOR activation is transduced through the mitogen-induced extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway and, to a much lesser degree, through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. Accordingly, whereas the low-dose PI3K inhibitor wortmannin and Akt inhibitor III profoundly inhibited Akt phosphorylation, they had a very modest effect on S6rp and 4E-BP1 phosphorylation. In turn, MEK inhibitors U0126 and PD98059 and siRNA-mediated depletion of either ERK1 or ERK2 inhibited S6rp phosphorylation much more effectively. Finally, the mTOR inhibitor rapamycin markedly decreased proliferation and increased the apoptotic rate of ALK+TCL cells. These findings identify mTOR as a novel key target of NPM/ALK and suggest that mTOR inhibitors may prove effective in therapy of ALK-induced malignancies. [on SciFinder(R)]

KW - tyrosine kinase NPM ALK mTOR signaling pathway cancer

U2 - 10.1038/sj.onc.1210346

DO - 10.1038/sj.onc.1210346

M3 - Journal article

VL - 26

SP - 5606

EP - 5614

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 38

ER -

ID: 202379063