Structural mapping of PEAK pseudokinase interactions identifies 14-3-3 as a molecular switch for PEAK3 signaling
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Date
2023
Authors
Roy, M.J.
Surudoi, M.G.
Kropp, A.
Hou, J.
Dai, W.
Hardy, J.M.
Liang, L.-Y.
Cotton, T.R.
Lechtenberg, B.C.
Dite, T.A.
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Journal article
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Nature Communications, 2023; 14(1):3542-1-3542-19
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Michael J. Roy, Minglyanna G. Surudoi, Ashleigh Kropp, Jianmei Hou, Weiwen Dai, Joshua M. Hardy, Lung-Yu Liang, Thomas R. Cotton, Bernhard C. Lechtenberg, Toby A. Dite, Xiuquan Ma, Roger J. Daly, Onisha Patel, Isabelle S. Lucet
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Abstract
PEAK pseudokinases regulate cell migration, invasion and proliferation by recruiting key signaling proteins to the cytoskeleton. Despite lacking catalytic activity, alteration in their expression level is associated with several aggressive cancers. Here, we elucidate the molecular details of key PEAK signaling interactions with the adapter proteins CrkII and Grb2 and the scaffold protein 14-3-3. Our findings rationalize why the dimerization of PEAK proteins has a crucial function in signal transduction and provide biophysical and structural data to unravel binding specificity within the PEAK interactome. We identify a conserved high affinity 14-3-3 motif on PEAK3 and demonstrate its role as a molecular switch to regulate CrkII binding and signaling via Grb2. Together, our studies provide a detailed structural snapshot of PEAK interaction networks and further elucidate how PEAK proteins, especially PEAK3, act as dynamic scaffolds that exploit adapter proteins to control signal transduction in cell growth/motility and cancer.
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© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.