Predictive Modeling of CDC25 Isoforms for Dual-action Phosphatase Substrate Specificity
DOI:
https://doi.org/10.47611/jsrhs.v12i4.5147Keywords:
cancer, cell cycle, phosphotase, oncogenic, tumor suppressive, protein modeling, Alpha FoldAbstract
Cancer is caused by a dysfunctional cell cycle that allows for excess cell division. The cell cycle is regulated by a series of kinases and phosphatases. Phosphatases are important proteins that remove phosphate groups from other proteins to induce a cellular response. CDC25 phosphatase and its isoforms, in particular, are phosphatases that play a key regulatory role in cell proliferation. However, research has shown that these phosphatases can play both an oncogenic and tumor suppressive function depending on the substrate that it is acting upon. This paper analyzes predictive protein interaction models between CDC25 isoforms and an oncogenic substrate, CDK1, and between a tumor suppressive substrate, CHEK2, to find hot spot residues which may have a role in substrate specificity. Identifying these interactions would identify potential targets for cancer therapies that could manipulate CDC25 phosphatases to exhibit tumor suppressive activity and while inhibiting its oncogenic activity.
Downloads
References or Bibliography
Blasina et al. (1999) A human homologue of the checkpoint kinase CDS1 directly inhibits cdc25 phosphatase. Cell Biol. 9(1):1-10. doi: 10.1016/s0960-9822(99)80041-4.
Boutros et al. (2007) Cdc25 phosphatases in cancer cells: Key players? good targets? Nat Rev Cancer. 7, 495–507 doi: 10.1038/nrc2169.
Brezak et al. (2004) A novel synthetic inhibitor of cdc25 phosphatases: BN82002. Cancer Res. 64(9):3320-5. doi: 10.1158/0008-5472.can-03-3984.
Cohen. (2002) The origins of protein phosphorylation. Nat Cell Biol. 4, E127-130. Doi: 10.1038/ncb0502-e127.
Fauman et al. (1998) Crystal structure of the catalytic domain of the human cell cycle control phosphatase, CDC25A. Cell. 93(4):617–625 doi: 10.1016/s0092-8674(00)81190-3.
Fischer. (2008) Chapter 11: Cell Cycle Inhibitors in Cancer: Current Status and Future Directions. Cancer Drug Design and Discovery, Elsevier Inc. 253-83.
Hausott and Klimaschewski. (2019). Promotion of peripheral nerve regeneration by stimulation of the ERK pathway. Anat Rec. 302(8):1261-1267. doi: 10.1002/ar.24126.
Hunt (2011). Getting In and Out of Mitosis*. Rambam Maimonides Med J. 2(3):e0051. doi: 10.5041/RMMJ.10051.
Landrieu et al. (2004) A small cdc25 dual-specificity tyrosine-phosphatase isoform in Arabidopsis thaliana. Proc Natl Acad Sci U S A. 101(36):13380–13385. doi: 10.1073/pnas.0405248101.
Liu et al. (2018) Identification of CDC25 as a common therapeutic target for triple-negative breast cancer. Cell Rep. 23(1):112–126. doi: 10.1016/j.celrep.2018.03.039.
Matthews et al. (2022) Cell cycle control in cancer. Nat Rev Mol Cell Biol. 23(1):74-88. doi: 10.1038/s41580-021-00404-3.
Moura and Conde. (2019) Phosphatases in Mitosis: Roles and Regulation. Biomolecules. 9(2):55 doi: 10.3390/biom9020055.
Narla et al. (2018) The impact of phosphatases on proliferative and survival signaling in cancer. Cellular Mol Life Sci. 75(15):2695–2718. doi: 10.1007/s00018-018-2826-8.
Ohouo and Smolka. (2012) The many roads to checkpoint activation. Cell Cycle. 11(24):4495. doi: 10.4161/cc.22933.
Perkins et al. (2010) Transient Protein-Protein Interactions: Structural, Functional, and Network Properties. Structure Rev. 18(10):1233-1243. doi: 10.1016/j.str.2010.08.007
Rudolph. (2007) Cdc25 phosphatases: structure, specificity, and mechanism. Biochemistry 46(12):3595–3604. doi: 10.1021/bi700026j
Shen and Huang. (2012) The role of cdc25a in the regulation of cell proliferation and apoptosis. Anticancer Agents Med Chem. 12(6):631-9. doi: 10.2174/187152012800617678.
Smolka et al. (2007) Proteome-wide identification of in vivo targets of DNA damage checkpoint kinases. Proc Natl Acad Sci U S A. 104(25):10364–10369 doi: 10.1073/pnas.0701622104.
Timofeev et al. (2010) Cdc25 phosphatases are required for timely assembly of CDK1-cyclin B at the G2/M transition. J Biol Chem. 285(22):16978-90. doi: 10.1074/jbc.M109.096552.
Published
How to Cite
Issue
Section
Copyright (c) 2023 Stuti Goel, Arianna Broad
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Copyright holder(s) granted JSR a perpetual, non-exclusive license to distriute & display this article.
