Receptor dynamics in cellular metabolism

Protein kinases play a central role in tumor progression, regulating fundamental processes such as angiogenesis, proliferation and metastasis. Various RTKs, including epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), and Tie1, are constitutively activated through amplification or mutation in numerous cancers. This leads to the activation of intracellular signaling pathways that modulate tumor cell proliferation, survival, invasiveness and neovascularization. Recently, RTK alterations have been associated with various metabolic adaptations in cancer cells. VEGFR2 signaling regulates glucose uptake and lactate production in ovarian and colorectal cancer while it triggers mitochondrial biogenesis in chemotherapy-exposed acute myeloid leukemia cells. Recently we demonstrated that the expression of the pro-oncogenic R1051Q mutation in VEGFR2 induces relevant metabolic changes in melanoma cells. The expression of VEGFR2R1051Q leads to higher energy metabolism and ATP production, and augments the dependence on glutamine (Gln) of melanoma cells increasing inGln uptake and the sensitivity to Gln deprivation. Thus, Gln addiction may be a metabolic vulnerability of tumors harboring the activating VEGFR2R1051Q mutation suggesting novel therapeutic approaches for those patients harboring activating mutations of VEGFR2. The organization and the non-homogenous both in space and time, distribution of lipids and proteins on the cell membrane appear highly dynamic at multiple spatial scales orchestrating the cellular response to different biochemical and mechanical inputs. In particular RTKs distribution and signaling are also governed by membrane dynamics. In this regard, we recently described that ligand/RTK interaction induces VEGFR2 redistribution on cell membrane, leading the relocation and the modulation of receptor activities in blood vessels during angiogenic and oncogenic events. Thus aberrant spatial regulation of RTKs may play a role in cancer progression.