| Structural highlights
6mtu is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | CL, EDO, PEG, PO4 |
| NonStd Res: | SEP |
| Gene: | SCRIB, CRIB1, KIAA0147, LAP4, SCRB1, VARTUL (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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] [CRCM_HUMAN] Candidate for the putative colorectal tumor suppressor gene located at 5q21. Suppresses cell proliferation and the Wnt/b-catenin pathway in colorectal cancer cells. Inhibits DNA binding of b-catenin/TCF/LEF transcription factors. Involved in cell migration independently of RAC1, CDC42 and p21-activated kinase (PAK) activation (PubMed:18591935, PubMed:19555689, PubMed:22480440). Represses the beta-catenin pathway (canonical Wnt signaling pathway) in a CCAR2-dependent manner by sequestering CCAR2 to the cytoplasm, thereby impairing its ability to inhibit SIRT1 which is involved in the deacetylation and negative regulation of beta-catenin (CTNB1) transcriptional activity (PubMed:24824780).[8] [9] [10] [11]
Publication Abstract from PubMed
Scribble is a crucial adaptor protein that plays a pivotal role during establishment and control of cell polarity, impacting many physiological processes ranging from cell migration to immunity and organization of tissue architecture. Scribble harbours a leucine-rich repeat domain and four PDZ domains that mediate most of Scribble's interactions with other proteins. It has become increasingly clear that post-translational modifications substantially impact Scribble-ligand interactions, with phosphorylation being a major modulator of binding to Scribble. To better understand how Scribble PDZ domains direct cell polarity signalling and how phosphorylation impacts this process, we investigated human Scribble interactions with MCC (Mutated in Colorectal Cancer). We systematically evaluated the ability of all four individual Scribble PDZ domains to bind the PDZ-binding motif (PBM) of MCC as well as MCC phosphorylated at the -1 Ser position. We show that Scribble PDZ1 and PDZ3 are the major interactors with MCC, and that modifications to Ser at the -1 position in the MCC PBM only has a minor effect on binding to Scribble PDZ domains. We then examined the structural basis for these observations by determining the crystal structures of Scribble PDZ1 domain bound to both the unphosphorylated MCC PBM as well as phosphorylated MCC. Our structures indicated that phospho-Ser at the -1 position in MCC is not involved in major contacts with Scribble PDZ1, and in conjunction with our affinity measurements suggest that the impact of phosphorylation at the -1 position of MCC must extend beyond a simple modulation of the affinity for Scribble PDZ domains.
Structural analysis of phosphorylation-associated interactions of human MCC with Scribble PDZ domains.,Caria S, Stewart BZ, Jin R, Smith BJ, Humbert PO, Kvansakul M FEBS J. 2019 Jul 18. doi: 10.1111/febs.15002. PMID:31317644[12]
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
- ↑ Fukuyama R, Niculaita R, Ng KP, Obusez E, Sanchez J, Kalady M, Aung PP, Casey G, Sizemore N. Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses beta-catenin-dependent transcription. Oncogene. 2008 Oct 9;27(46):6044-55. doi: 10.1038/onc.2008.204. Epub 2008 Jun 30. PMID:18591935 doi:https://dx.doi.org/10.1038/onc.2008.204
- ↑ Arnaud C, Sebbagh M, Nola S, Audebert S, Bidaut G, Hermant A, Gayet O, Dusetti NJ, Ollendorff V, Santoni MJ, Borg JP, Lecine P. MCC, a new interacting protein for Scrib, is required for cell migration in epithelial cells. FEBS Lett. 2009 Jul 21;583(14):2326-32. doi: 10.1016/j.febslet.2009.06.034. Epub , 2009 Jun 24. PMID:19555689 doi:https://dx.doi.org/10.1016/j.febslet.2009.06.034
- ↑ Pangon L, Van Kralingen C, Abas M, Daly RJ, Musgrove EA, Kohonen-Corish MR. The PDZ-binding motif of MCC is phosphorylated at position -1 and controls lamellipodia formation in colon epithelial cells. Biochim Biophys Acta. 2012 Jun;1823(6):1058-67. doi:, 10.1016/j.bbamcr.2012.03.011. Epub 2012 Mar 28. PMID:22480440 doi:https://dx.doi.org/10.1016/j.bbamcr.2012.03.011
- ↑ Pangon L, Mladenova D, Watkins L, Van Kralingen C, Currey N, Al-Sohaily S, Lecine P, Borg JP, Kohonen-Corish MR. MCC inhibits beta-catenin transcriptional activity by sequestering DBC1 in the cytoplasm. Int J Cancer. 2015 Jan 1;136(1):55-64. doi: 10.1002/ijc.28967. Epub 2014 May 27. PMID:24824780 doi:https://dx.doi.org/10.1002/ijc.28967
- ↑ Caria S, Stewart BZ, Jin R, Smith BJ, Humbert PO, Kvansakul M. Structural analysis of phosphorylation-associated interactions of human MCC with Scribble PDZ domains. FEBS J. 2019 Jul 18. doi: 10.1111/febs.15002. PMID:31317644 doi:https://dx.doi.org/10.1111/febs.15002
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