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Cited by 49Protein Kinase Regulation and GTPase SignalingUbiquitin and proteasome pathwaysCellular transport and secretion

Negative Regulation of EGFR-Vav2 Signaling Axis by Cbl Ubiquitin Ligase Controls EGF Receptor-mediated Epithelial Cell Adherens Junction Dynamics and Cell Migration

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Duan, Lei, Raja, Srikumar M., Chen, Gengsheng, Virmani, Sumeet, Williams, Stetson H., Clubb, Robert J., Mukhopadhyay, Chandrani, Rainey, Mark A. +7 more·2011·Journal of Biological Chemistry
DOI 10.1074/jbc.m110.188086PMC PMC3013022
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Abstract

The E3 ubiquitin ligase Casitas B lymphoma protein (Cbl) controls the ubiquitin-dependent degradation of EGF receptor (EGFR), but its role in regulating downstream signaling elements with which it associates and its impact on biological outcomes of EGFR signaling are less clear. Here, we demonstrate that stimulation of EGFR on human mammary epithelial cells disrupts adherens junctions (AJs) through Vav2 and Rac1/Cdc42 activation. In EGF-stimulated cells, Cbl regulates the levels of phosphorylated Vav2 thereby attenuating Rac1/Cdc42 activity. Knockdown of Cbl and Cbl-b enhanced the EGF-induced disruption of AJs and cell motility. Overexpression of constitutively active Vav2 activated Rac1/Cdc42 and reorganized junctional actin cytoskeleton; these effects were suppressed by WT Cbl and enhanced by a ubiquitin ligase-deficient Cbl mutant. Cbl forms a complex with phospho-EGFR and phospho-Vav2 and facilitates phospho-Vav2 ubiquitinylation. Cbl can also interact with Vav2 directly in a Cbl Tyr-700-dependent manner. A ubiquitin ligase-deficient Cbl mutant enhanced the morphological transformation of mammary epithelial cells induced by constitutively active Vav2; this effect requires an intact Cbl Tyr-700. These results indicate that Cbl ubiquitin ligase plays a critical role in the maintenance of AJs and suppression of cell migration through down-regulation of EGFR-Vav2 signaling.

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  • EGFR activity status has been linked to intercellular junctional and actomyosin organization and function.

    “As EGFR activity status has been linked to intercellular junctional and actomyosin organization and function26–29”

    From E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning (2017) · cites this paper as [27]

    The Results report that EGFR signaling reorganized junctional actin and disrupted adherens junctions in human mammary epithelial cells. The cited passages do not establish an effect on myosin or actomyosin function, so that part of the claim goes beyond what this paper shows. (LLM, conf=0.83)

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Cited by

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Authors
Duan, L., Raja, S. M., Chen, G., Virmani, S., Williams, S. H., Clubb, R. J., Mukhopadhyay, C., Rainey, M. A., Ying, G., Dimri, M., Chen, J., Reddi, A. L., Naramura, M., Band, V., & Band, H.
Affiliations
Northwestern University (US)
Corresponding author
  • Duan, Lei
  • Raja, Srikumar M.
  • Band, Hamid
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2011-01
Volume
286
Issue
1
Pages
620-633
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m110.188086
PMC
PMC3013022
OpenAlex
W2026132614
Cited by
49
References
2
Citations by year
2026: 1 · 2025: 4 · 2024: 3 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 4 · 2016: 7 · 2015: 1 · 2014: 9 · 2013: 4 · 2012: 3
FWCI
1.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Defense (W81XWH, W81XWH0710351)
  • U.S. Department of Health and Human Services
  • University of Nebraska Medical Center
  • Nebraska Department of Health and Human Services (LB506)
  • National Institutes of Health (W81XWH, CA87986)
  • National Cancer Institute (CA 94143, CA 116552, R01CA099163, R01CA094143, CA 96844, R01CA096844, CA105489, R01CA105489, CA 87986, R01CA087986, R01CA116552, CA 99163)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
CBL, EGF receptor, Vav2, Rac1, Cdc42, adherens junctions, cell migration, ubiquitination, E3 ubiquitin ligase, mammary epithelial cells, actin cytoskeleton, EGFR signaling
MeSH terms
Actins, Amino Acid Sequence, Animals, Cell Adhesion, Cell Line, Cell Movement, Cytoskeleton, Enzyme Activation, Epidermal Growth Factor, Epithelial Cells, Humans, Molecular Sequence Data, Mutation, Phosphorylation, Signal Transduction, cdc42 GTP-Binding Protein, rac1 GTP-Binding Protein, Protein Transport, Adherens Junctions, Proto-Oncogene Proteins c-cbl, Mice, Proto-Oncogene Proteins c-vav, Ubiquitination, ErbB Receptors

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