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ARF1 controls the activation of the PI3K pathway to regulate EGF dependent growth and migration of breast cancer cells. |
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AbstractActivation of intracellular signaling pathways by growth factors is one of the major causes of cancer development and progression. Recent studies have demonstrated that monomeric G proteins of the Ras family are key regulators of cell proliferation, migration, and invasion. Using an invasive breast cancer cell lines, we demonstrate that the ADP-ribosylation factor 1 (ARF1), a small GTPase classically associated with the Golgi, is an important regulator of the biological effects induced by epidermal growth factor (EGF). Here, we show that this ARF isoform is activated following EGF stimulation and that in MDA-MB-231 cells, ARF1 is found in dynamic plasma membrane ruffles. Inhibition of endogenous ARF1 expression results in the inhibition of breast cancer cell migration and proliferation. The underlying mechanism involves the activation of the phosphatidylinositol-3 kinase (PI3K) pathway. Our data demonstrate that depletion of ARF1 markedly impairs the recruitment of the PI3K catalytic subunit (p110a) to the plasma membrane, and the association of the regulatory subunit (p85a) to the activated receptor. These results uncover a novel molecular mechanism by which ARF1 regulates breast cancer cell growth and invasion during cancer progression.
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