| Structural highlights
Function
ECT2_HUMAN Guanine nucleotide exchange factor (GEF) that catalyzes the exchange of GDP for GTP. Promotes guanine nucleotide exchange on the Rho family members of small GTPases, like RHOA, RHOC, RAC1 and CDC42. Required for signal transduction pathways involved in the regulation of cytokinesis. Component of the centralspindlin complex that serves as a microtubule-dependent and Rho-mediated signaling required for the myosin contractile ring formation during the cell cycle cytokinesis. Regulates the translocation of RHOA from the central spindle to the equatorial region. Plays a role in the control of mitotic spindle assembly; regulates the activation of CDC42 in metaphase for the process of spindle fibers attachment to kinetochores before chromosome congression. Involved in the regulation of epithelial cell polarity; participates in the formation of epithelial tight junctions in a polarity complex PARD3-PARD6-protein kinase PRKCQ-dependent manner. Plays a role in the regulation of neurite outgrowth. Inhibits phenobarbital (PB)-induced NR1I3 nuclear translocation. Stimulates the activity of RAC1 through its association with the oncogenic PARD6A-PRKCI complex in cancer cells, thereby acting to coordinately drive tumor cell proliferation and invasion. Also stimulates genotoxic stress-induced RHOB activity in breast cancer cells leading to their cell death.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]
Publication Abstract from PubMed
Epithelial cell transforming 2 (Ect2) protein activates Rho GTPases and controls cytokinesis and many other cellular processes. Dysregulation of Ect2 is associated with various cancers. Here, we report the crystal structure of human Ect2 and complementary mechanistic analyses. The data show the C-terminal PH domain of Ect2 folds back and blocks the canonical RhoA-binding site at the catalytic center of the DH domain, providing a mechanism of Ect2 autoinhibition. Ect2 is activated by binding of GTP-bound RhoA to the PH domain, which suggests an allosteric mechanism of Ect2 activation and a positive-feedback loop reinforcing RhoA signaling. This bimodal RhoA binding of Ect2 is unusual and was confirmed with Forster resonance energy transfer (FRET) and hydrogen-deuterium exchange mass spectrometry (HDX-MS) analyses. Several recurrent cancer-associated mutations map to the catalytic and regulatory interfaces, and dysregulate Ect2 in vitro and in vivo. Together, our findings provide mechanistic insights into Ect2 regulation in normal cells and under disease conditions.
Structure and regulation of human epithelial cell transforming 2 protein.,Chen M, Pan H, Sun L, Shi P, Zhang Y, Li L, Huang Y, Chen J, Jiang P, Fang X, Wu C, Chen Z Proc Natl Acad Sci U S A. 2020 Jan 14;117(2):1027-1035. doi:, 10.1073/pnas.1913054117. Epub 2019 Dec 30. PMID:31888991[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Tatsumoto T, Xie X, Blumenthal R, Okamoto I, Miki T. Human ECT2 is an exchange factor for Rho GTPases, phosphorylated in G2/M phases, and involved in cytokinesis. J Cell Biol. 1999 Nov 29;147(5):921-8. PMID:10579713
- ↑ Saito S, Liu XF, Kamijo K, Raziuddin R, Tatsumoto T, Okamoto I, Chen X, Lee CC, Lorenzi MV, Ohara N, Miki T. Deregulation and mislocalization of the cytokinesis regulator ECT2 activate the Rho signaling pathways leading to malignant transformation. J Biol Chem. 2004 Feb 20;279(8):7169-79. Epub 2003 Nov 25. PMID:14645260 doi:10.1074/jbc.M306725200
- ↑ Liu XF, Ishida H, Raziuddin R, Miki T. Nucleotide exchange factor ECT2 interacts with the polarity protein complex Par6/Par3/protein kinase Czeta (PKCzeta) and regulates PKCzeta activity. Mol Cell Biol. 2004 Aug;24(15):6665-75. PMID:15254234 doi:10.1128/MCB.24.15.6665-6675.2004
- ↑ Kim JE, Billadeau DD, Chen J. The tandem BRCT domains of Ect2 are required for both negative and positive regulation of Ect2 in cytokinesis. J Biol Chem. 2005 Feb 18;280(7):5733-9. Epub 2004 Nov 15. PMID:15545273 doi:10.1074/jbc.M409298200
- ↑ Oceguera-Yanez F, Kimura K, Yasuda S, Higashida C, Kitamura T, Hiraoka Y, Haraguchi T, Narumiya S. Ect2 and MgcRacGAP regulate the activation and function of Cdc42 in mitosis. J Cell Biol. 2005 Jan 17;168(2):221-32. Epub 2005 Jan 10. PMID:15642749 doi:10.1083/jcb.200408085
- ↑ Yuce O, Piekny A, Glotzer M. An ECT2-centralspindlin complex regulates the localization and function of RhoA. J Cell Biol. 2005 Aug 15;170(4):571-82. PMID:16103226 doi:10.1083/jcb.200501097
- ↑ Liu XF, Ohno S, Miki T. Nucleotide exchange factor ECT2 regulates epithelial cell polarity. Cell Signal. 2006 Oct;18(10):1604-15. Epub 2006 Feb 21. PMID:16495035 doi:10.1016/j.cellsig.2006.01.007
- ↑ Kamijo K, Ohara N, Abe M, Uchimura T, Hosoya H, Lee JS, Miki T. Dissecting the role of Rho-mediated signaling in contractile ring formation. Mol Biol Cell. 2006 Jan;17(1):43-55. Epub 2005 Oct 19. PMID:16236794 doi:10.1091/mbc.E05-06-0569
- ↑ Hara T, Abe M, Inoue H, Yu LR, Veenstra TD, Kang YH, Lee KS, Miki T. Cytokinesis regulator ECT2 changes its conformation through phosphorylation at Thr-341 in G2/M phase. Oncogene. 2006 Jan 26;25(4):566-78. PMID:16170345 doi:10.1038/sj.onc.1209078
- ↑ Asiedu M, Wu D, Matsumura F, Wei Q. Centrosome/spindle pole-associated protein regulates cytokinesis via promoting the recruitment of MyoGEF to the central spindle. Mol Biol Cell. 2009 Mar;20(5):1428-40. doi: 10.1091/mbc.E08-01-0001. Epub 2009, Jan 7. PMID:19129481 doi:10.1091/mbc.E08-01-0001
- ↑ Justilien V, Fields AP. Ect2 links the PKCiota-Par6alpha complex to Rac1 activation and cellular transformation. Oncogene. 2009 Oct 15;28(41):3597-607. doi: 10.1038/onc.2009.217. Epub 2009 Jul, 20. PMID:19617897 doi:10.1038/onc.2009.217
- ↑ Wolfe BA, Takaki T, Petronczki M, Glotzer M. Polo-like kinase 1 directs assembly of the HsCyk-4 RhoGAP/Ect2 RhoGEF complex to initiate cleavage furrow formation. PLoS Biol. 2009 May 5;7(5):e1000110. doi: 10.1371/journal.pbio.1000110. Epub 2009, May 26. PMID:19468300 doi:10.1371/journal.pbio.1000110
- ↑ Justilien V, Jameison L, Der CJ, Rossman KL, Fields AP. Oncogenic activity of Ect2 is regulated through protein kinase C iota-mediated phosphorylation. J Biol Chem. 2011 Mar 11;286(10):8149-57. doi: 10.1074/jbc.M110.196113. Epub 2010, Dec 28. PMID:21189248 doi:10.1074/jbc.M110.196113
- ↑ Srougi MC, Burridge K. The nuclear guanine nucleotide exchange factors Ect2 and Net1 regulate RhoB-mediated cell death after DNA damage. PLoS One. 2011 Feb 23;6(2):e17108. doi: 10.1371/journal.pone.0017108. PMID:21373644 doi:10.1371/journal.pone.0017108
- ↑ Chen M, Pan H, Sun L, Shi P, Zhang Y, Li L, Huang Y, Chen J, Jiang P, Fang X, Wu C, Chen Z. Structure and regulation of human epithelial cell transforming 2 protein. Proc Natl Acad Sci U S A. 2020 Jan 14;117(2):1027-1035. doi:, 10.1073/pnas.1913054117. Epub 2019 Dec 30. PMID:31888991 doi:http://dx.doi.org/10.1073/pnas.1913054117
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