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The WW domain of IQGAP1 binds directly to the p110α catalytic subunit of PI 3-kinase
Open accessPreprint — published as 10.1042/bcj20220493
Abstract
IQGAP1 is a multi-domain cancer-associated protein that serves as a scaffold protein for multiple signaling pathways. Numerous binding partners have been found for the calponin homology, IQ and GAP-related domains in IQGAP1. Identification of a binding partner for its WW domain has proven elusive, however, even though a cell-penetrating peptide derived from this domain has marked anti-tumor activity. Here, using in vitro binding assays with human proteins and co-precipitation from human cells, we show that the WW domain of human IQGAP1 binds directly to the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K). In contrast, the WW domain does not bind to ERK1/2, MEK1/2, or the p85α regulatory subunit of PI3K when p85α is expressed alone. However, the WW domain is able to bind to the p110α/p85α heterodimer when both subunits are co-expressed, as well as to the mutationally activated p110α/p65α heterodimer. We present a model of the structure of the IQGAP1 WW domain, and experimentally identify key residues in the hydrophobic core and beta strands of the WW domain that are required for binding to p110α. These findings contribute to a more precise understanding of IQGAP1-mediated scaffolding, and of how IQGAP1-derived therapeutic peptides might inhibit tumorigenesis.
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Highly accurate protein structure prediction with AlphaFold
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Metadata
- Authors
- Bardwell, A. J., Paul, M., Yoneda, K. C., Andrade-Ludeña, M. D., Nguyen, O. T., Fruman, D. A., & Bardwell, L.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Bardwell, Lee
- Venue
- Biochemical Journal
- Publisher
- openRxiv
- Published
- 2022-09-25
- Volume
- 480
- Issue
- 10
- Pages
- 729-750
- ISSN
- 0264-6021 (ISSN-L)
- PMC
- PMC10625650
- OpenAlex
- W4372291501
- Cited by
- 4
- References
- 1
- Citations by year
- 2026: 4
- FWCI
- 0.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Biochemical Journal (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion, other-oa)
- Funders
- Cancer Research Coordinating Committee (CTR-20-637218)
- National Institutes of Health (UL1TR001414)
- University of California, Irvine (UL1 TR001414, P30CA‐062203)
- National Cancer Institute (P30CA062203)
- National Center for Research Resources (Grant UL1 TR001414)
- National Center for Advancing Translational Sciences (Grant UL1 TR001414, TR001414)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 14-3-3 protein interactions
- Keywords
- IQGAP1, WW domain, p110α, phosphatidylinositol 3-kinase, protein-protein interaction, scaffold proteins, p85α, ERK1/2, MEK1/2, cell-penetrating peptides, hydrophobic core, beta-strand, carcinogenesis, tumor-associated proteins
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