Naslov
Regulation of Ras activity in cellular feeding

Autori
Filić, Vedrana

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
“HDIR-6: Targeting Cancer”, 6th Meeting of the Croatian Association for Cancer Research : Book of Abstracts / Ozretić, Petar - Zagreb : Hrvatsko društvo za istraživanje raka (HDIR), 2022, 6-6

ISBN
978-953-48672-1-1

Skup
6th Meeting of the Croatian Association for Cancer Research

Mjesto i datum
Zagreb, Hrvatska, 10.11.2022. - 12.11.2022

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
IqgC ; RasGAP ; Ras ; macropinocytosis

Sažetak
Cellular feeding and proliferation are major processes required for the growth of an organism. Nevertheless, uncontrolled cell growth is a hallmark of cancer. Macropinocytosis or “cellular drinking” is nonselective, bulk uptake of large volumes of extracellular fluid. For unicellular organisms like an amoeba, macropinocytosis is a way of nutrient uptake. In a metazoan organism, cells preferentially import nutrients via cell surface transporters or by receptor-mediated endocytosis, while macropinocytosis is used by specialized cells for other purposes. Although all tested mammalian cell lines are capable of performing stimulated macropinocytosis in cell culture, it is still not clear whether and to what extent is macropinocytosis used by mammalian cells as s nutrient uptake pathway. However, tumor cells often exploit macropinocytosis to obtain macromolecules as a nutrient source and thus thrive in the microenvironment that is often scarce in glucose and amino acids due to poor tumor vascularization. In particular, malignant cells harboring mutated oncogenic Ras proteins perform constitutive macropinocytosis similar to amoeba Dictyostelium discoideum. Hence, mammalian and D. discoideum cells in culture are the most widely used models to study macropinocytic uptake. We investigated D. discoideum protein IqgC and showed that it negatively regulates macropinocytosis by inhibiting Ras activity. IqgC acts as a RasGAP (Ras GTPase activating protein) that specifically deactivates RasG, a GTPase crucial for efficient fluid uptake in D. discoideum. The negative effect was more pronounced in wild-type D. discoideum strain that contains another RasGAP, NF1, a homolog of a human RasGAP neurofibromin 1, and thus has more suppressed macropinocytosis. Deletion of IqgC in this genetic background induced more elevated fluid uptake compared to NF1 deficient strain. IqgC strongly accumulates at forming and nascent macropinosomes where it colocalizes with the active Ras probe. However, Ras dissociates from the internalized vesicle prior to IqgC. We demonstrated that RasG is indispensable for the recruitment of IqgC to the forming cup, but other proteins seem to be required for its retention during early macropinosome maturation. One candidate is another GTPase from the Ras superfamily, Rab5A which is a direct interactor of IqgC. The biological significance of this interaction is currently under investigation.

Izvorni jezik
Engleski

Znanstvena područja
Biologija

POVEZANOST RADA