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. 2012:2012:123253.
doi: 10.1155/2012/123253. Epub 2012 Jul 18.

NPM-ALK: The Prototypic Member of a Family of Oncogenic Fusion Tyrosine Kinases

Affiliations

NPM-ALK: The Prototypic Member of a Family of Oncogenic Fusion Tyrosine Kinases

Joel D Pearson et al. J Signal Transduct. 2012.

Abstract

Anaplastic lymphoma kinase (ALK) was first identified in 1994 with the discovery that the gene encoding for this kinase was involved in the t(2;5)(p23;q35) chromosomal translocation observed in a subset of anaplastic large cell lymphoma (ALCL). The NPM-ALK fusion protein generated by this translocation is a constitutively active tyrosine kinase, and much research has focused on characterizing the signalling pathways and cellular activities this oncoprotein regulates in ALCL. We now know about the existence of nearly 20 distinct ALK translocation partners, and the fusion proteins resulting from these translocations play a critical role in the pathogenesis of a variety of cancers including subsets of large B-cell lymphomas, nonsmall cell lung carcinomas, and inflammatory myofibroblastic tumours. Moreover, the inhibition of ALK has been shown to be an effective treatment strategy in some of these malignancies. In this paper we will highlight malignancies where ALK translocations have been identified and discuss why ALK fusion proteins are constitutively active tyrosine kinases. Finally, using ALCL as an example, we will examine three key signalling pathways activated by NPM-ALK that contribute to proliferation and survival in ALCL.

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Figures

Figure 1
Figure 1
The STAT3 signalling pathway in ALK+ ALCL. STAT3 is activated by NPM-ALK signalling, but reports differ as to whether this is JAK3-dependent or independent. The phosphatase, PP2A, and signalling through the IL-9, IL-21, and IL-22 receptors also promote STAT3 activation in ALK+ ALCL. STAT3 promotes the expression of genes that suppress apoptosis and enhance proliferation in ALK+ ALCL. STAT3 can also repress a variety of genes in this malignancy through DNA methylation. Suppression of the SHP1 phosphatase by STAT3 is particularly important in ALK+ ALCL, as SHP1 inhibits NPM-ALK and STAT3 activity.
Figure 2
Figure 2
The MEK/ERK signalling pathway in ALK+ ALCL. NPM-ALK activates Ras, Raf-1, MEK1/2, and ERK1/2. The ability of NPM-ALK to activate MEK/ERK appears not to be dependent on Raf-1. Rather, another MAP3K, Cot, may be important for activation of MEK/ERK in ALK+ ALCL, but it is not known whether Cot is activated by NPM-ALK signalling. The activation of ERK1/2 promotes ALK+ ALCL proliferation and survival, largely through the JunB transcription factor and serine/threonine kinase, mTOR. ERK1/2 activates the ETS-1 transcription factor which promotes the transcription of JunB. JunB promotes the transcription of CD30 and Granzyme B in this lymphoma, but likely has other important targets that have not yet been identified. ERK1/2 are thought to activate mTOR signalling in ALK+ ALCL by phosphorylating and inhibiting TSC1/2. mTOR phosphorylates and inhibits the cell cycle inhibitor, Rb. It also phosphorylates and activates p70S6K which phosphorylates RPS6 to promote cell growth. mTOR also influences the expression of genes that contribute to the survival and proliferation of ALK+ ALCL cells. MEK/ERK are also activated by signalling through CD30 in ALK+ ALCL, and this leads to enhanced CD30 expression.
Figure 3
Figure 3
The PI3K/Akt signalling pathway in ALK+ ALCL. NPM-ALK associates with and activates PI3K, which, in turn, activates the serine/threonine kinase Akt. Expression of the PTEN lipid phosphatase, which inhibits PI3K signalling, is lost in some ALK+ ALCL tumour samples and likely contributes to Akt activation in cancers where PTEN is not expressed. Akt inhibits GSK3β activity in ALK+ ALCL, which protects GLI1, Mcl-1, and CDC25A from proteasomal degradation. Akt also phosphorylates the cell-cycle inhibitor, p27kip1, in ALK+ ALCL and this results in the targeting of p27kip1 for proteasomal degradation. Phosphorylation of the FOXO3a transcription factor by Akt results in the binding of FOXO3a to 14-3-3 proteins. This sequesters FOXO3a in the cytoplasm, preventing it from translocating to the nucleus and transcribing pro-apoptotic and cell cycle inhibitory genes. In addition to being an important downstream target of MEK/ERK signalling in ALK+ ALCL, mTOR activity may also be promoted by PI3K/Akt signalling. NPM-ALK/Akt signalling also promotes the expression of SHH. When SHH binds its receptor, Patched (PTCH), this relieves the inhibition of the Smoothened (SMO) coreceptor by Patched. This allows Smoothened to activate the GLI1 transcription factor, which promotes the transcription of the proproliferation protein, Cyclin D2.

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