The working model shows that under normal oxygen tension GNAQ/GNA11 mutations, present in the Gα subunit of heterotrimeric G proteins (GPCR: G protein-coupled receptors) in the majority of primary uveal melanomas, are responsible for the activation of MAPK pathway under normoxic conditions. MAPK pathway in turn activates mTOR signaling, known to regulate HIF-1α protein translation and tumor growth. In hypoxic conditions, HIF-1α protein levels are further induced by the inhibition of its oxygen-dependent degradation. Such induction leads to Notch1 intracellular domain (NICD1) stabilization and Notch activation. The induction of P-Erk and P-Akt, mediated by a non-canonical Notch signaling, contributes in promoting invasion and metastasis.