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Cited by 75Cellular transport and secretionProtein Kinase Regulation and GTPase SignalingCaveolin-1 and cellular processes

RalA-Exocyst Complex Regulates Integrin-Dependent Membrane Raft Exocytosis and Growth Signaling

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Balasubramanian, Nagaraj, Meier, Jeremy A., Scott, David W., Norambuena, Andrés, White, Michael A., Schwartz, Martin Alexander·2010·Current Biology
DOI 10.1016/j.cub.2009.11.016PMC PMC2822103
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Abstract

Anchorage dependence of cell growth is a key metastasis-suppression mechanism that is mediated by effects of integrins on growth signaling pathways. The small GTPase RalA is activated in metastatic cancers through multiple mechanisms and specifically induces anchorage independence. Loss of integrin-mediated adhesion triggers caveolin-dependent internalization of cholesterol- and sphingolipid-rich lipid raft microdomains to the recycling endosomes; these domains serve as platforms for many signaling pathways, and their clearance from the plasma membrane (PM) after cell detachment suppresses growth signaling. Conversely, readhesion triggers their return to the PM and restores growth signaling. Activation of Arf6 by integrins mediates exit of raft markers from the recycling endosomes but is not sufficient for return to the PM. We now show that RalA but not RalB mediates integrin-dependent membrane raft exocytosis through the exocyst complex. Constitutively active RalA restores membrane raft targeting to promote anchorage-independent growth signaling. Ras-transformed pancreatic cancer cells also show RalA-dependent constitutive PM raft targeting. These results identify RalA as a key determinant of integrin-dependent membrane raft trafficking and regulation of growth signaling. They therefore define a mechanism by which RalA regulates anchorage dependence and provide a new link between integrin signaling and cancer.

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  • Ral is required for lipid raft exocytosis and spreading of murine embryonic fibroblasts on fibronectin-coated coverslips.

    “Ral is required for lipid raft exocytosis and spreading of murine embryonic fibroblasts (MEFs) on fibronectin-coated coverslips20.”

    From Discovery and characterization of small molecules that target the GTPase Ral (2014) · cites this paper as [20]

    The Results and Discussion sections on Ral inhibition and RalA/RalB knockdown report that inhibiting RalA delayed lipid-raft return and spreading of WT murine embryonic fibroblasts replated on fibronectin-coated surfaces. The copy identifies those surfaces as fibronectin-coated but does not establish that they were coverslips; it also says spreading was delayed, not completely blocked. No page number is available in the indexed passages. (LLM, conf=0.82)

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  • Ral promotes anchorage-independence.

    “Ral promotes anchorage-independence1,20, therefore we measured cell growth in soft agar.”

    From Discovery and characterization of small molecules that target the GTPase Ral (2014) · cites this paper as [20]

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Research works printed but not linked: 27

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Authors
Balasubramanian, N., Meier, J. A., Scott, D. W., Norambuena, A., White, M. A., & Schwartz, M. A.
Affiliations
  • University of Virginia (US)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
Balasubramanian, Nagaraj
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
2010-01
Volume
20
Issue
1
Pages
75-79
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/j.cub.2009.11.016
PMC
PMC2822103
OpenAlex
W2008838494
Cited by
75
References
0
Citations by year
2026: 1 · 2025: 5 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 9 · 2019: 2 · 2018: 4 · 2017: 5 · 2016: 7 · 2015: 3 · 2014: 5 · 2013: 3 · 2012: 11
FWCI
3.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (T32HL007284)
  • National Cancer Institute (R01CA071443)
  • National Institute of General Medical Sciences (R01GM047214)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
Keywords
RalA, exocyst complex, integrins, lipid rafts, anchorage-independent growth, cell adhesion, growth signaling, recycling endosomes, ARF6, caveolin, cholesterol, sphingolipids, pancreatic cancer, metastasis
MeSH terms
Animals, Base Sequence, Cell Adhesion, Cells, Cultured, Exocytosis, Mutation, Signal Transduction, Integrins, ral GTP-Binding Proteins, Membrane Microdomains, RNA, Small Interfering, Cell Proliferation, Caveolin 1, Mice

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