A1 Refereed original research article in a scientific journal
The guanine nucleotide exchange factor VAV3 participates in ERBB4-mediated cancer cell migration
Authors: Ojala VK, Knittle AM, Kirjalainen P, Merilahti JAM, Kortesoja M, Tvorogov D, Vaparanta K, Lin SJ, Kast J, Pulliainen AT, Kurppa KJ, Elenius K
Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Publication year: 2020
Journal: Journal of Biological Chemistry
Journal name in source: JOURNAL OF BIOLOGICAL CHEMISTRY
Journal acronym: J BIOL CHEM
Volume: 295
Issue: 33
First page : 11559
Last page: 11571
Number of pages: 13
ISSN: 0021-9258
DOI: https://doi.org/10.1074/jbc.RA119.010925
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/49962055
ERBB4 is a member of the epidermal growth factor receptor (EGFR)/ERBB subfamily of receptor tyrosine kinases that regulates cellular processes including proliferation, migration, and survival. ERBB4 signaling is involved in embryogenesis and homeostasis of healthy adult tissues, but also in human pathologies such as cancer, neurological disorders, and cardiovascular diseases. Here, an MS-based analysis revealed the Vav guanine nucleotide exchange factor 3 (VAV3), an activator of Rho family GTPases, as a critical ERBB4-interacting protein in breast cancer cells. We confirmed the ERBB4-VAV3 interaction by targeted MS and coimmunoprecipitation experiments and further defined it by demonstrating that kinase activity and Tyr-1022 and Tyr-1162 of ERBB4, as well as the intact phosphotyrosine-interacting SH2 domain of VAV3, are necessary for this interaction. We found that ERBB4 stimulates tyrosine phosphorylation of the VAV3 activation domain, known to be required for guanine nucleotide exchange factor (GEF) activity of VAV proteins. In addition to VAV3, the other members of the VAV family, VAV1 and VAV2, also coprecipitated with ERBB4. Analyses of the effects of overexpression of dominant-negative VAV3 constructs or shRNA-mediated down-regulation of VAV3 expression in breast cancer cells indicated that active VAV3 is involved in ERBB4-stimulated cell migration. These results define the VAV GEFs as effectors of ERBB4 activity in a signaling pathway relevant for cancer cell migration.
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