NPM-ALK: The Prototypic Member of a Family of Oncogenic Fusion Tyrosine Kinases
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, , in ALK+ ALCL and this results in the targeting of 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.
