Project 3. EGFR signaling network adaptations to overcome RAS-induced membrane stress in glioblastoma
Co-Leads
Research
Receptor tyrosine kinases (RTKs) such as EGFR drive oncogenic RAS (HRAS, NRAS, KRAS) signaling and are widely amplified in glioblastoma, but these brain cancers are interestingly incapable of tolerating unbridled signaling from mutant RAS. Forced RAS hyperactivity causes excessive vacuolization and macropinocytosis, giving rise to a “death by drinking” phenotype termed methuosis. This phenotype is not unique to glioblastoma, suggesting a general stress on endomembranes and plasma-membrane internalization when RAS is chronically hyperactivated in an unbalanced fashion. Since EGFR activates RAS along with membrane-dependent AKT (AKT1, AKT2, AKT3) signaling, it implies that EGFR-amplified cells must identify strategies to ameliorate membrane stress during glioblastomagenesis. The hypothesis of Project 3 is that glioblastomas rebalance RAS activity by altering intracellular traffic of EGFR itself and location-dependent signaling of the protein tyrosine phosphatase SHP2. Glioblastomas are known to acquire vIII deletions in EGFR that render it deficient in internalization and endolysosomal degradation. SHP2 (PTPN11) is capable of transmitting RAS-activating signals between internalized EGFR and the plasma membrane, but links to glioblastoma phenotypes are just beginning to emerge. Systems complexity lies in the tandem SH2 domains of SHP2, which compete for phosphotyrosines on active EGFR with other activators of ERK (SHC1, GAB1), AKT (PIK3R1, PIK3R2), and alternative pathways (PLCG1). The specific aims are to 1) define the key intermolecular interactions in the EGFR signaling network and mechanistically predict the consequences of network adaptations to EGFRvIII expression; 2) map differential EGFR signaling network activation among glioblastoma cells to the methuosis phenotype through a hybrid mechanistic and data-driven computational model; and 3) test model-derived predictions about signaling control of methuosis in vitro and in vivo using new tools to monitor RAS–ERK and AKT activities concurrently and noninvasively. Significance of Project 3 extends past methuosis as a niche phenotype, because RTK–SHP2 signaling at the plasma membrane impacts the response of glioblastomas to DNA-damaging therapeutics.
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