Figure 1.

PI3K signaling feedbacks: PI3K signaling is highly activated and de-regulated in GEP‑NENs. Several feedback loops contribute to this effect ³³⁰, ³³¹. RTK activation by ligand binding triggers a phosphorylation cascade onto IRS-1 and PI3K. The latter phosphorylates PIP2 and thereby activates PDK-1 and Akt at T308. Akt in turn inhibits TSC2 by phosphorylation, which leads to mTOR activation. The mTOR complex 1 activates translation via eIF4A and p70S6K and cell cycle progression, whereas mTORC2 relieves a feedback loop by fully-activating Akt at S273. S6K promotes a negative feedback onto IRS‑1 and thereby counteracts mTORC1 inhibition. The two major negative regulators, PTEN and TSC2 are frequently down regulated in GEP-NENs which lead to a highly deregulated Akt activation ³³, ¹²⁸.