| Structural highlights
Disease
SCRIB_HUMAN The disease is caused by mutations affecting the gene represented in this entry.
Function
SCRIB_HUMAN Scaffold protein involved in different aspects of polarized cells differentiation regulating epithelial and neuronal morphogenesis. Most probably functions in the establishment of apico-basal cell polarity. May function in cell proliferation regulating progression from G1 to S phase and as a positive regulator of apoptosis for instance during acinar morphogenesis of the mammary epithelium. May also function in cell migration and adhesion and hence regulate cell invasion through MAPK signaling. May play a role in exocytosis and in the targeting synaptic vesicles to synapses. Functions as an activator of Rac GTPase activity.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Scribble (Scrib) is a highly conserved cell polarity regulator that harbours potent tumour suppressor activity and plays an important role in cell migration. Dysregulation of polarity is associated with poor prognosis during viral infections. Human T-cell lymphotrophic virus-1 (HTLV-1) encodes for the oncogenic Tax1 protein, a modulator of the transcription of viral and human proteins that can cause cell cycle dysregulation as well as a loss of genomic integrity. Previous studies established that Scribble interacts with Tax1 via its C-terminal PDZ-binding motif (PBM), leading to aggregation of polarity regulators and subsequent perturbation of host cell adhesion, proliferation, and signalling. Using isothermal titration calorimetry, we now show that all four PDZ domains of Scribble bind to Tax1 PBM. We then determined crystal structures of Scribble PDZ1, PDZ2 and PDZ3 domains bound to Tax1 PBM. Our findings establish a structural basis for Tax1-mediated subversion of Scribble-mediated cell polarity signalling and provide the platform for mechanistic studies to examine Tax1 induced mislocalization of Scribble and the associated changes in cellular architecture and subsequent tumorigenesis.
Structural insight into the Scribble PDZ domains interaction with the oncogenic Human T-cell lymphotrophic virus-1 (HTLV-1) Tax1 PBM.,Javorsky A, Maddumage JC, Mackie ERR, Soares da Costa TP, Humbert PO, Kvansakul M FEBS J. 2022 Aug 27. doi: 10.1111/febs.16607. PMID:36029163[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Audebert S, Navarro C, Nourry C, Chasserot-Golaz S, Lecine P, Bellaiche Y, Dupont JL, Premont RT, Sempere C, Strub JM, Van Dorsselaer A, Vitale N, Borg JP. Mammalian Scribble forms a tight complex with the betaPIX exchange factor. Curr Biol. 2004 Jun 8;14(11):987-95. PMID:15182672 doi:10.1016/j.cub.2004.05.051
- ↑ Lahuna O, Quellari M, Achard C, Nola S, Meduri G, Navarro C, Vitale N, Borg JP, Misrahi M. Thyrotropin receptor trafficking relies on the hScrib-betaPIX-GIT1-ARF6 pathway. EMBO J. 2005 Apr 6;24(7):1364-74. Epub 2005 Mar 17. PMID:15775968 doi:10.1038/sj.emboj.7600616
- ↑ Qin Y, Capaldo C, Gumbiner BM, Macara IG. The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin. J Cell Biol. 2005 Dec 19;171(6):1061-71. Epub 2005 Dec 12. PMID:16344308 doi:10.1083/jcb.200506094
- ↑ Nagasaka K, Nakagawa S, Yano T, Takizawa S, Matsumoto Y, Tsuruga T, Nakagawa K, Minaguchi T, Oda K, Hiraike-Wada O, Ooishi H, Yasugi T, Taketani Y. Human homolog of Drosophila tumor suppressor Scribble negatively regulates cell-cycle progression from G1 to S phase by localizing at the basolateral membrane in epithelial cells. Cancer Sci. 2006 Nov;97(11):1217-25. Epub 2006 Sep 5. PMID:16965391 doi:10.1111/j.1349-7006.2006.00315.x
- ↑ Dow LE, Elsum IA, King CL, Kinross KM, Richardson HE, Humbert PO. Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling. Oncogene. 2008 Oct 9;27(46):5988-6001. doi: 10.1038/onc.2008.219. Epub 2008 Jul, 21. PMID:18641685 doi:10.1038/onc.2008.219
- ↑ Nola S, Sebbagh M, Marchetto S, Osmani N, Nourry C, Audebert S, Navarro C, Rachel R, Montcouquiol M, Sans N, Etienne-Manneville S, Borg JP, Santoni MJ. Scrib regulates PAK activity during the cell migration process. Hum Mol Genet. 2008 Nov 15;17(22):3552-65. doi: 10.1093/hmg/ddn248. Epub 2008 Aug, 20. PMID:18716323 doi:10.1093/hmg/ddn248
- ↑ Zhan L, Rosenberg A, Bergami KC, Yu M, Xuan Z, Jaffe AB, Allred C, Muthuswamy SK. Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell. 2008 Nov 28;135(5):865-78. doi: 10.1016/j.cell.2008.09.045. PMID:19041750 doi:10.1016/j.cell.2008.09.045
- ↑ Javorsky A, Maddumage JC, Mackie ERR, Soares da Costa TP, Humbert PO, Kvansakul M. Structural insight into the Scribble PDZ domains interaction with the oncogenic Human T-cell lymphotrophic virus-1 (HTLV-1) Tax1 PBM. FEBS J. 2022 Aug 27. doi: 10.1111/febs.16607. PMID:36029163 doi:http://dx.doi.org/10.1111/febs.16607
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