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Cited by 71Protein Kinase Regulation and GTPase SignalingCellular transport and secretionCellular Mechanics and Interactions

The RalB Small GTPase Mediates Formation of Invadopodia through a GTPase-Activating Protein-Independent Function of the RalBP1/RLIP76 Effector

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Neel, Nicole F., Rossman, Kent L., Martin, Timothy D., Hayes, Tikvah K., Yeh, Jen Jen, Der, Channing J.·2012·Molecular and Cellular Biology
DOI 10.1128/mcb.06291-11PMC PMC3318593
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Abstract

Our recent studies implicated key and distinct roles for the highly related RalA and RalB small GTPases (82% sequence identity) in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis and invasive and metastatic growth, respectively. How RalB may promote PDAC invasion and metastasis has not been determined. In light of known Ral effector functions in regulation of actin organization and secretion, we addressed a possible role for RalB in formation of invadopodia, actin-rich membrane protrusions that contribute to tissue invasion and matrix remodeling. We determined that a majority of KRAS mutant PDAC cell lines exhibited invadopodia and that expression of activated K-Ras is both necessary and sufficient for invadopodium formation. Invadopodium formation was not dependent on the canonical Raf-MEK-ERK effector pathway and was instead dependent on the Ral effector pathway. However, this process was more dependent on RalB than on RalA. Surprisingly, RalB-mediated invadopodium formation was dependent on RalBP1/RLIP76 but not Sec5 and Exo84 exocyst effector function. Unexpectedly, the requirement for RalBP1 was independent of its best known function as a GTPase-activating protein for Rho small GTPases. Instead, disruption of the ATPase function of RalBP1 impaired invadopodium formation. Our results identify a novel RalB-mediated biochemical and signaling mechanism for invadopodium formation.

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  • The activity of the RhoGAP domain is abolished by mutations of a conserved arginine finger (R232) and a stabilizing lysine residue (K268).

    “The activity of the RhoGAP domain is abolished by mutations of a conserved arginine finger (R232) and a stabilizing lysine residue (K268) (50).”

    From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [50]

    The Results (page not provided) identify R232 as the arginine finger and K268 as a conserved lysine in the RalBP1 RhoGAP domain. They report that the R232A/K268A double mutant failed to enhance Cdc42 GTP hydrolysis, unlike the wild-type domain. Our copy does not describe K268 as stabilizing or establish that either mutation alone abolishes activity. (LLM, conf=0.86)

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Authors
Neel, N. F., Rossman, K. L., Martin, T. D., Hayes, T. K., Yeh, J. J., & Der, C. J.
Affiliations
  • UNC Lineberger Comprehensive Cancer Center (US)
  • University of North Carolina at Chapel Hill (US)
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2012-04-01
Volume
32
Issue
8
Pages
1374-1386
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.06291-11
PMC
PMC3318593
OpenAlex
W2019761859
Cited by
71
References
2
Citations by year
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FWCI
2.31
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • UNC Libraries
Funders
  • American Cancer Society
  • Vanderbilt University
  • National Institutes of Health (5r01ca042978-30)
  • School of Medicine, Vanderbilt University
  • National Cancer Institute (CA042978, R01-CA042978, R01CA140424, T32CA071341, CA140424)
  • National Institute of General Medical Sciences (T32GM007040)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
RalB, RalA, invadopodia, pancreatic ductal adenocarcinoma, KRAS mutation, tumor invasion, metastasis, exocyst, Sec5, ATPase activity, actin organization, extracellular matrix remodeling
MeSH terms
Enzyme Activation, Humans, Neoplasm Invasiveness, Pancreatic Neoplasms, Signal Transduction, ATP-Binding Cassette Transporters, GTPase-Activating Proteins, ral GTP-Binding Proteins, Carcinoma, Pancreatic Ductal, Cell Surface Extensions, Cell Line, Tumor

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