Going Rogue: Mechanisms, Regulation, and Roles of Mutationally Activated G in Human Cancer.

G protein-coupled receptors (GPCRs) couple to heterotrimeric G proteins, comprised of and γ subunits, to convert extracellular signals into activation of intracellular signaling pathways. Canonically, GPCR-mediated activation results in the exchange of GDP for GTP on G protein subunits (G) and the dissociation of G-GTP and G protein subunits (G), both of which can regulate a variety of signaling pathways. Hydrolysis of bound GTP by G returns the protein to G-GDP and allows reassociation with G to reform the inactive heterotrimer.

Disruption of the interaction between mutationally activated Gα and Gβγ attenuates aberrant signaling.

Heterotrimeric G protein stimulation via G protein-coupled receptors promotes downstream proliferative signaling. Mutations can occur in Gα proteins which prevent GTP hydrolysis; this allows the G proteins to signal independently of G protein-coupled receptors and can result in various cancers, such as uveal melanoma (UM). Most UM cases harbor Q209L, Q209P, or R183C mutations in Gα proteins, rendering the proteins constitutively active (CA).

Enhanced membrane binding of oncogenic G protein αqQ209L confers resistance to inhibitor YM-254890.

Heterotrimeric G proteins couple activated G protein-coupled receptors (GPCRs) to intracellular signaling pathways. They can also function independently of GPCR activation upon acquiring mutations that prevent GTPase activity and result in constitutive signaling, as occurs with the αqQ209L mutation in uveal melanoma. YM-254890 (YM) can inhibit signaling by both GPCR-activated WT αq and GPCR-independent αqQ209L.

Developing a State University System Model to Diversify Faculty in the Biomedical Sciences.

Amid increasing demands from students and the public, universities have recently reinvigorated their efforts to increase the number of faculty from underrepresented populations. Although a myriad of piecemeal programs targeting individual recruitment and development have been piloted at several institutions, overall growth in faculty diversity remains almost negligible and highly localized. To bring about genuine change, we hypothesize a consortia approach that links individuals to hiring opportunities within a state university system might be more effective.