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

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.