Figure 1.

Schematic representation of the signaling in GIST. KIT and PDGFRA mutant GIST cases are characterized by gain-of-function mutations that activate the tyrosine kinase receptor in a constitutive and ligand-independent manner. KIT and PDGFRA WT GIST cases do not present gain-of-function alterations but may overexpress IGF1R. KIT, PDGFRA and IGF1R are tyrosine kinase receptors and their activation results in the promotion of downstream cascades, including PtdIns(3,4,5)P₃-MTOR, JAK-JUN and RAS-MAPK/ERK, which lead to uncontrolled cell proliferation and growth, survival and inhibition of apoptosis. KIT and PDGFRA WT GIST, in addition, can harbor mutations in 1 of the 4 subunits of the SDH gene, which cause loss of function. This leads to cytoplasmatic accumulation of succinate, which downregulates prolyl hydroxylase, responsible for promoting HIF1A degradation. Succinate accumulation results in increased levels of HIF1A, which enters the nucleus and activates transcription factors.