Journal
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
Volume 1873, Issue 1, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbcan.2020.188337
Keywords
RLIP; Drug-resistance; Glutathione-conjugate transport; Clathrin-dependent endocytosis
Categories
Funding
- United States Department of Defense [W81XWH-16-1-0641]
- National Cancer Institute of the National Institutes of Health [P30CA33572]
- Beckman Research Institute of City of Hope
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RLIP (Ral-interacting protein) is a multifunctional protein that couples ATP hydrolysis with the movement of substances. Its primary function appears to be in the plasma membrane, where it catalyzes the ATP-dependent efflux of glutathione-conjugates (GS-Es), as well as un-metabolized drugs and toxins. In the plasma membrane, its interaction with the clathrin adaptor protein AP2 localizes it to endocytic vesicle, where its GS-E-stimulated ATPase and transport activity are required for clathrin-dependent endocytosis (CDE). CDE is an essential mechanism for internalizing ligand-receptor complexes that signal proliferation (EGF, insulin, IGF1), apoptosis (TNF alpha, TRAIL, Fas-L), and differentiation and morphogenesis (TGF beta, WNT, Notch, SHH). Aberrant functioning of these pathways appears crucial for most cancer cells to evade apoptosis, invade surrounding tissues, and metastasize. Internalization of receptor-ligand complexes by CDE begins a sequence of events that can terminate, initiate, or modulate downstream signaling; the consequences of signaling through these downstream pathways may be inherently different in cancer and normal cells, a view supported by numerous basic and clinical observations. In this review, we will discuss the GS-E transport activity of RLIP, which determines the rate of ligand endocytosis, and how the inhibition and/or depletion of RLIP globally disrupts in ligand-receptor signaling.
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