Piquing our interest: Insights into the role of PEAK3 in signaling and disease

doi:10.1126/scisignal.abm9396

Comment

. 2022 Feb 22;15(722):eabm9396.

doi: 10.1126/scisignal.abm9396. Epub 2022 Feb 22.

Piquing our interest: Insights into the role of PEAK3 in signaling and disease

Michael D Paul¹, Hayarpi Torosyan¹, Natalia Jura^{1

2}

Affiliations

¹ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
² Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.

PMID: 35192418
PMCID: PMC9288111
DOI: 10.1126/scisignal.abm9396

Comment

Piquing our interest: Insights into the role of PEAK3 in signaling and disease

Michael D Paul et al. Sci Signal. 2022.

. 2022 Feb 22;15(722):eabm9396.

doi: 10.1126/scisignal.abm9396. Epub 2022 Feb 22.

Authors

Michael D Paul¹, Hayarpi Torosyan¹, Natalia Jura^{1

2}

Affiliations

¹ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
² Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.

PMID: 35192418
PMCID: PMC9288111
DOI: 10.1126/scisignal.abm9396

Abstract

Pseudokinases are critical signaling hubs that are increasingly appreciated as important disease targets. In this issue of Science Signaling, Hou et al. bring new insights into the signaling mechanisms of the pseudokinase PEAK3 by characterizing its epidermal growth factor-dependent interactome and demonstrating oncogenic effects of PEAK3 overexpression.

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Conflict of interest statement

Competing interests: N.J. is a member of the SAB of Turning Point Therapeutics, SUDO Biosciences, and Type6 Therapeutics; a shareholder of Turning Point Therapeutics and stock option holder of SUDO Biosciences and Type6 Therapeutics; and a cofounder and shareholder of Rezo Therapeutics.

Figures

**Figure 1.. Regulation of PEAK3 signaling by protein-protein interactions.**
**(A)** Rewiring of PEAK3 interactome as a function of EGF stimulation. The strength of association of different binding partners with PEAK3 is correlated with the cartoon darkness: weak interactions are faded away. pY denotes phospho-Tyr²⁴ of PEAK3. **(B)** Summary of differential signaling outcomes of PEAK3 homo- and heterodimerization with PEAK1 and PEAK2, as described in the Hou *et al*. (7).

See this image and copyright information in PMC

Comment on

Distinct PEAK3 interactors and outputs expand the signaling potential of the PEAK pseudokinase family.
Hou J, Nguyen EV, Surudoi M, Roy MJ, Patel O, Lucet IS, Ma X, Daly RJ. Hou J, et al. Sci Signal. 2022 Feb 22;15(722):eabj3554. doi: 10.1126/scisignal.abj3554. Epub 2022 Feb 22. Sci Signal. 2022. PMID: 35192416

Cited by

Location, location, location: Protein kinase nanoclustering for optimised signalling output.
Gormal RS, Martinez-Marmol R, Brooks AJ, Meunier FA. Gormal RS, et al. Elife. 2024 Jan 11;13:e93902. doi: 10.7554/eLife.93902. Elife. 2024. PMID: 38206309 Free PMC article. Review.
Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3.
Torosyan H, Paul MD, Forget A, Lo M, Diwanji D, Pawłowski K, Krogan NJ, Jura N, Verba KA. Torosyan H, et al. Nat Commun. 2023 Jun 19;14(1):3543. doi: 10.1038/s41467-023-38864-0. Nat Commun. 2023. PMID: 37336883 Free PMC article.

References

1. Wang Y, Kelber JA, Tran Cao HS, Cantin GT, Lin R, Wang W, Kaushal S, Bristow JM, Edgington TS, Hoffman RM, Bouvet M, Yates III JR, Klemke RL, Pseudopodium-enriched atypical kinase 1 regulates the cytoskeleton and cancer progression. PNAS 107, 10920–10925 (2010) - PMC - PubMed
1. Zheng Y, Zhang C, Croucher DR, Soliman MA, St-Denis N, Pasculescu A, Taylor L, Tate SA, Hardy WR, Colwill K, Dai AY, Bagshaw R, Dennis JW, Gingras A-C, Daly RJ, Pawson T, Temporal regulation of EGF signalling networks by the scaffold protein Shc1. Nat. 499, 166–171 (2013). - PMC - PubMed
1. Senda Y, Murata-Kamiya N, Hatakeyama M, C-terminal Src kinase-mediated EPIYA phosphorylation of Pragmin creates a feed-forward C-terminal Src kinase activation loop that promotes cell motility. Cancer Sci. 107, 972–980 (2016) - PMC - PubMed
1. Patel O, Roy MJ, Murphy JM, Lucet IS, The PEAK family of pseudokinases, their role in cell signalling and cancer. FEBS J. 287, 4183–4197 (2020). - PubMed
1. Lecointre C, Simon V, Kerneur C, Allemand F, Fournet A, Montarras I, Pons J-L, Gelin M, Brignatz C, Urbach S, Labesse G, Roche S, Dimerization of the Pragmin pseudo-kinase regulates protein tyrosine phosphorylation. Structure 26, 545–554 (2018) - PubMed

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[1] Wang Y, Kelber JA, Tran Cao HS, Cantin GT, Lin R, Wang W, Kaushal S, Bristow JM, Edgington TS, Hoffman RM, Bouvet M, Yates III JR, Klemke RL, Pseudopodium-enriched atypical kinase 1 regulates the cytoskeleton and cancer progression. PNAS 107, 10920–10925 (2010) - PMC - PubMed

[2] Wang Y, Kelber JA, Tran Cao HS, Cantin GT, Lin R, Wang W, Kaushal S, Bristow JM, Edgington TS, Hoffman RM, Bouvet M, Yates III JR, Klemke RL, Pseudopodium-enriched atypical kinase 1 regulates the cytoskeleton and cancer progression. PNAS 107, 10920–10925 (2010) - PMC - PubMed

[3] Zheng Y, Zhang C, Croucher DR, Soliman MA, St-Denis N, Pasculescu A, Taylor L, Tate SA, Hardy WR, Colwill K, Dai AY, Bagshaw R, Dennis JW, Gingras A-C, Daly RJ, Pawson T, Temporal regulation of EGF signalling networks by the scaffold protein Shc1. Nat. 499, 166–171 (2013). - PMC - PubMed

[4] Zheng Y, Zhang C, Croucher DR, Soliman MA, St-Denis N, Pasculescu A, Taylor L, Tate SA, Hardy WR, Colwill K, Dai AY, Bagshaw R, Dennis JW, Gingras A-C, Daly RJ, Pawson T, Temporal regulation of EGF signalling networks by the scaffold protein Shc1. Nat. 499, 166–171 (2013). - PMC - PubMed

[5] Senda Y, Murata-Kamiya N, Hatakeyama M, C-terminal Src kinase-mediated EPIYA phosphorylation of Pragmin creates a feed-forward C-terminal Src kinase activation loop that promotes cell motility. Cancer Sci. 107, 972–980 (2016) - PMC - PubMed

[6] Senda Y, Murata-Kamiya N, Hatakeyama M, C-terminal Src kinase-mediated EPIYA phosphorylation of Pragmin creates a feed-forward C-terminal Src kinase activation loop that promotes cell motility. Cancer Sci. 107, 972–980 (2016) - PMC - PubMed

[7] Patel O, Roy MJ, Murphy JM, Lucet IS, The PEAK family of pseudokinases, their role in cell signalling and cancer. FEBS J. 287, 4183–4197 (2020). - PubMed

[8] Patel O, Roy MJ, Murphy JM, Lucet IS, The PEAK family of pseudokinases, their role in cell signalling and cancer. FEBS J. 287, 4183–4197 (2020). - PubMed

[9] Lecointre C, Simon V, Kerneur C, Allemand F, Fournet A, Montarras I, Pons J-L, Gelin M, Brignatz C, Urbach S, Labesse G, Roche S, Dimerization of the Pragmin pseudo-kinase regulates protein tyrosine phosphorylation. Structure 26, 545–554 (2018) - PubMed

[10] Lecointre C, Simon V, Kerneur C, Allemand F, Fournet A, Montarras I, Pons J-L, Gelin M, Brignatz C, Urbach S, Labesse G, Roche S, Dimerization of the Pragmin pseudo-kinase regulates protein tyrosine phosphorylation. Structure 26, 545–554 (2018) - PubMed

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Piquing our interest: Insights into the role of PEAK3 in signaling and disease

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Piquing our interest: Insights into the role of PEAK3 in signaling and disease

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