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Cited by 120Drug Transport and Resistance MechanismsPharmacogenetics and Drug MetabolismGlutathione Transferases and Polymorphisms

Transport of glutathione conjugates and chemotherapeutic drugs by RLIP76 (RALBP1): A novel link between G-protein and tyrosine kinase signaling and drug resistance

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Awasthi, Sanjay, Singhal, Sharad S., Sharma, Rajendra, Zimniak, Piotr, Awasthi, Yogesh C.·2003·International Journal of Cancer
DOI 10.1002/ijc.11260
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Abstract

Our studies have shown that RLIP76 (RALBP1), a 76 kDa Ral‐binding, Rho/Rac‐GAP and Ral effector protein, is a novel multispecific transporter of xenobiotics as well as GS‐Es. Like previously characterized ABC transporters, it mediates ATP‐dependent transport of structurally unrelated amphiphilic xenobiotics and displays inherent ATPase activity, which is stimulated by its substrate allocrites. It does not have significant sequence homology with ABC transporters and differs from the ABC transporters in several other important aspects, including (i) lack of any close homologs in humans, (ii) lack of a classical Walker domain, (iii) integral membrane association without clearly defined transmembrane domains and (iv) its role as a direct link to Ras/Ral/Rho and EGF‐R signaling through its multifunctional nature, including GAP activity, regulation of exocytosis as well as clathrin‐coated pit–mediated receptor endocytosis. Its multifunctional nature derives from the presence of multiple motifs, including a Rho/Rac GAP domain, a Ral effector domain binding motif, 2 distinct ATP‐binding domains, a H+‐ATPase domain, PKC and tyrosine kinase phosphorylation sites and the ability to undergo fragmentation into multiple smaller peptides which participate as components of macromolecular functional complexes. One of the physiologic functions of RLIP76 is regulation of intracellular concentration of the electrophilic intermediates of oxidative lipid metabolism by mediating efflux of GS‐E formed from oxidative degradation of arachidonic acid, including leukotrienes and the 4HNE‐GSH conjugate. RLIP76‐mediated transport of amphiphilic chemotherapeutic agents such as anthracyclines and vinca alkaloids as well as GS‐E produced during oxidative metabolism places this multifunctional protein in a central role as a resistance mechanism for preventing apoptosis caused by chemotherapeutic agents and a variety of external/internal stressors, including oxidative stress, heat shock and radiation. © 2003 Wiley‐Liss, Inc.

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  • Rlip is a stress-protective ATPase of the mercapturic acid pathway that couples clathrin-dependent endocytosis with the efflux of glutathione-electrophile conjugates.

    “Rlip is a stress-protective ATPase of the mercapturic acid pathway that couples clathrin-dependent endocytosis with the efflux of glutathione–electrophile conjugates.”

    From Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease? (2022) · cites this paper as [1]

    The Abstract identifies RLIP76 as an ATPase that exports glutathione–electrophile conjugates and helps protect against oxidative and other stressors. The section “An Integrated Model for the Role of RALBP1 in Signaling” describes coupling that efflux to endocytosis as a hypothesis, not an established function. The copy does not explicitly identify RLIP76 as an ATPase of the mercapturic acid pathway. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Rlip has roles in cellular mechanisms requiring membrane fusion, including CDE and exocytosis.

    “Rlip has been reported to have roles in several cellular mechanisms which require membrane fusion events, including CDE and exocytosis [1].”

    From Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease? (2022) · cites this paper as [1]

    The sections ‘Signaling Downstream of RALBP1’ and ‘An Integrated Model for the Role of RALBP1 in Signaling’ link RLIP76/RALBP1 to clathrin-dependent receptor endocytosis and discuss its role in exocytosis. They do not establish the additional characterization that both processes require membrane fusion events. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Awasthi, S., Singhal, S. S., Sharma, R., Zimniak, P., & Awasthi, Y. C.
Affiliations
  • The University of Texas at Arlington (US)
  • The University of Texas Medical Branch at Galveston (US)
  • Central Arkansas Veterans Healthcare System (US)
ORCID
Singhal, Sharad S.
Venue
International Journal of Cancer
Publisher
Wiley
Published
2003-06-03
Volume
106
Issue
5
Pages
635-646
ISSN
  • 0020-7136 (ISSN-L)
  • 1097-0215
DOI
10.1002/ijc.11260
OpenAlex
W1994023206
Cited by
120
References
0
Citations by year
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FWCI
0.74
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • International Journal of Cancer (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (CA 77495, R01CA077495)
  • National Institute of General Medical Sciences (GM-32304, R01GM032304)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
Keywords
RLIP76, RALBP1, glutathione S-conjugates, chemoresistance, drug efflux, ATP-dependent transport, EGF receptor signaling, anthracyclines, vinca alkaloids, apoptosis, xenobiotic transport
MeSH terms
Adenosine Triphosphatases, Animals, Antibiotics, Antineoplastic, Biological Transport, Carrier Proteins, Drug Resistance, Glutathione, Humans, Protein-Tyrosine Kinases, Vinca Alkaloids, Xenobiotics, Signal Transduction, ATP-Binding Cassette Transporters, GTP-Binding Proteins, GTP Phosphohydrolases, GTPase-Activating Proteins

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