SCRIB

SCRIB, also known as Scribble, SCRIBL, or Scribbled homolog (Drosophila), is a scaffold protein which in humans is encoded by the SCRIB gene. It was originally isolated in Drosophila melanogaster in a pathway (also known as the Scribble complex) with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae) as a tumor suppressor. In humans, SCRIB is found as a membrane protein and is involved in cell migration, cell polarity, and cell proliferation in epithelial cells. There is also strong evidence that SCRIB may play a role in cancer progression because of its strong homology to the Drosophila protein.

SCRIB
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1UJU, 1WHA, 1X5Q, 2W4F, 4WYU, 4WYT
Identifiers
Aliases	SCRIB, CRIB1, SCRB1, SCRIB1, Vartul, scribbled planar cell polarity protein, scribble planar cell polarity protein, oSCRIB
External IDs	OMIM: 607733; MGI: 2145950; HomoloGene: 44228; GeneCards: SCRIB; OMA:SCRIB - orthologs
Gene location (Human) Chr. Chromosome 8 (human) Band 8q24.3 Start 143,790,920 bp End 143,815,773 bp
Gene location (Mouse) Chr. Chromosome 15 (mouse) Band 15 D3|15 35.29 cM Start 75,919,007 bp End 75,941,633 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right uterine tube skin of abdomen mucosa of transverse colon skin of leg vagina Amygdala ventricular zone tibial nerve C1 segment minor salivary glands Top expressed in otic vesicle saccule otic placode spermatocyte seminiferous tubule lip ventricular zone internal carotid artery spermatid neural layer of retina More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding guanylate kinase activity ionotropic glutamate receptor binding cadherin binding Cellular component postsynaptic membrane cell projection membrane cell-cell junction adherens junction plasma membrane nucleoplasm myelin sheath abaxonal region cell junction cell leading edge presynapse extracellular exosome presynaptic membrane lamellipodium Scrib-APC-beta-catenin complex cytoplasm cell-cell contact zone ionotropic glutamate receptor complex postsynaptic density basolateral plasma membrane synapse glutamatergic synapse extrinsic component of postsynaptic density membrane Biological process cell differentiation establishment of apical/basal cell polarity synaptic vesicle targeting activation of GTPase activity astrocyte cell migration apoptotic process involved in morphogenesis wound healing auditory receptor cell morphogenesis mammary gland duct morphogenesis auditory receptor cell stereocilium organization multicellular organism development neural tube closure synaptic vesicle endocytosis protein localization to adherens junction positive regulation of apoptotic process positive chemotaxis morphogenesis of embryonic epithelium cell population proliferation viral process cell migration cochlear nucleus development negative regulation of mitotic cell cycle positive regulation of receptor recycling chemical synaptic transmission receptor clustering establishment or maintenance of epithelial cell apical/basal polarity GMP metabolic process GDP metabolic process receptor localization to synapse neurotransmitter receptor transport, endosome to postsynaptic membrane neurotransmitter receptor transport postsynaptic membrane to endosome suppression by virus of host type I interferon-mediated signaling pathway suppression by virus of host innate immune response suppression by virus of host JAK-STAT cascade via inhibition of STAT1 activity suppression by virus of host JAK-STAT cascade via inhibition of STAT2 activity cell-cell adhesion protein localization vesicle-mediated transport in synapse regulation of postsynaptic neurotransmitter receptor internalization post-anal tail morphogenesis inner ear receptor cell stereocilium organization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 23513 105782 Ensembl ENSG00000274287 ENSG00000180900 ENSMUSG00000022568 UniProt Q14160 Q80U72 RefSeq (mRNA) NM_182706 NM_015356 NM_134089 NM_001310542 NM_001310543 RefSeq (protein) NP_056171 NP_874365 NP_001297471 NP_001297472 NP_598850 Location (UCSC) Chr 8: 143.79 – 143.82 Mb Chr 15: 75.92 – 75.94 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

For the early portable computer, see Scrib.

Function

In Drosophila melanogaster, SCRIB is involved in synaptic function, neuroblast differentiation, and epithelial polarization. Mechanistically, the human homolog is a scaffold protein linked to cellular differentiation centered on the regulation of epithelial as well as neuronal morphogenesis. Deficiency in SCRIB impairs many aspects of cell polarity and cell movement. SCRIB is also likely involved in establishing apical-basal polarity as well as progression from the G1 phase to S phase in the cell cycle as a result of its relationship with cell proliferation and exocytosis.

The transcribed protein products of the SCRIB gene along with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae) are components of the Scribble complex that is localized in the basolateral membrane. The Scribble complex plays a role in determining cell polarity and cell proliferation in epithelial cells. The precise mechanism by which these proteins function together is currently unknown, but they have been implicated in several signaling pathways, vesicle trafficking, and in the myosin II-actin cytoskeleton. The Scribble complex has been shown to promote basolateral membrane identity by antagonizing both the Par complex and the Crumbs complex, which promote apical membrane identity. These genes have also been identified as tumor suppressors in Drosophila melanogaster. Since these genes are highly conserved in humans, there is evidence that they play a role in cancer progression.

Structure

The human homolog is a LAP protein, it contains 16 leucine-rich repeats and four PDZ domains. SCRIB belongs to a protein complex containing betaPIX, an exchange factor for Rac/Cdc42, and GIT1, a GTPase activating protein for ARF6 implicated in receptor recycling and exocytosis.

Subcellular and tissue distribution

SCRIB is found in the cell membrane most often as a peripheral membrane protein. The Scribble complex is localized at the basolateral membrane. SCRIB is also found in cellular junctions such as adherens junctions and tight junctions. Specifically, it is located in the kidney, skeletal muscles, liver, lung, breast, intestine, placenta and epithelial cells.

Clinical significance

The PDZ domain of SCRIB binds directly to the human papillomavirus E6 protein. SCRIB is targeted for ubiquitination by a complex of E6 and UBE3A and E6 induces degradation of SCRIB.

Role as a tumor suppressor

As mentioned above, SCRIB has been identified as a tumor suppressor along with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae). Specifically, SCRIB deficient mutants have been shown to promote the activity of numerous oncogenes. For example, SCRIB is known to inhibit breast cancer formation and the depletion of SCRIB promotes neoplastic growth by disrupting morphogenesis and inhibiting cell death through an association with Myc. In human cells expressing oncogenic Ras or Raf, it was found the loss of SCRIB resulted in the invasion of the extracellular matrix by various cell types. This is believed to be a direct result of regulation of the MAP Kinase pathway by SCRIB.

Role in epithelial mesenchymal transition (EMT)

Due to its role in cell polarity and cell motility, SCRIB has also been implicated in epithelial mesenchymal transition (EMT), which is linked to tumor metastasis and proliferation in many cancers. EMT is implicated in cancer progression by allowing static epithelial cells to become migratory and allowing these cells to adapt to as well as colonize new environments. In cancerous epithelial tissues, SCRIB is found primarily in the cytosol as opposed to its usual location in the membrane, thus further implicating a role in tumor progression and EMT for SCRIB.

Knockdown mutants have resulted in the loss of adhesion between Madin-Darby canine kidney epithelial cells. This loss of adhesion was correlated with an acquired mesenchymal appearance, an increase in motility, and loss of directionality. These effects were a direct result of the interruption of E-cadherin-mediated cellular adhesion. A decrease in cell migration and an overall decrease in cell motility markers as well as epithelial mesenchymal transition mediators was also observed in small lung adenocarcinoma cells that were depleted of SCRIB.

Further reading

• Nakajima D, Okazaki N, Yamakawa H, et al. (2003). "Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones". DNA Res. 9 (3): 99–106. doi:10.1093/dnares/9.3.99. PMID 12168954.
• Nagase T, Seki N, Tanaka A, et al. (1996). "Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1". DNA Res. 2 (4): 167–74, 199–210. doi:10.1093/dnares/2.4.167. PMID 8590280.
• Nakagawa S, Huibregtse JM (2000). "Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase". Mol. Cell. Biol. 20 (21): 8244–53. doi:10.1128/MCB.20.21.8244-8253.2000. PMC 86433. PMID 11027293.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Dow LE, Brumby AM, Muratore R, et al. (2004). "hScrib is a functional homologue of the Drosophila tumour suppressor Scribble". Oncogene. 22 (58): 9225–30. doi:10.1038/sj.onc.1207154. PMID 14681682.
• Nakagawa S, Yano T, Nakagawa K, et al. (2004). "Analysis of the expression and localisation of a LAP protein, human scribble, in the normal and neoplastic epithelium of uterine cervix". Br. J. Cancer. 90 (1): 194–9. doi:10.1038/sj.bjc.6601465. PMC 2395302. PMID 14710229.
• Bouwmeester T, Bauch A, Ruffner H, et al. (2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nat. Cell Biol. 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216. S2CID 11683986.
• Brill LM, Salomon AR, Ficarro SB, et al. (2004). "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry". Anal. Chem. 76 (10): 2763–72. doi:10.1021/ac035352d. PMID 15144186.
• Lehner B, Sanderson CM (2004). "A protein interaction framework for human mRNA degradation". Genome Res. 14 (7): 1315–23. doi:10.1101/gr.2122004. PMC 442147. PMID 15231747.
• Borg JP (2004). "[hScrib: a potential novel tumor suppressor]". Pathol. Biol. 52 (6): 328–31. doi:10.1016/j.patbio.2003.09.015. PMID 15261375.
• Beausoleil SA, Jedrychowski M, Schwartz D, et al. (2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proc. Natl. Acad. Sci. U.S.A. 101 (33): 12130–5. Bibcode:2004PNAS..10112130B. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.
• Ballif BA, Villén J, Beausoleil SA, et al. (2005). "Phosphoproteomic analysis of the developing mouse brain". Mol. Cell. Proteomics. 3 (11): 1093–101. doi:10.1074/mcp.M400085-MCP200. PMID 15345747.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Petit MM, Meulemans SM, Alen P, et al. (2006). "The tumor suppressor Scrib interacts with the zyxin-related protein LPP, which shuttles between cell adhesion sites and the nucleus". BMC Cell Biol. 6 (1): 1. doi:10.1186/1471-2121-6-1. PMC 546208. PMID 15649318.
• Barrios-Rodiles M, Brown KR, Ozdamar B, et al. (2005). "High-throughput mapping of a dynamic signaling network in mammalian cells". Science. 307 (5715): 1621–5. Bibcode:2005Sci...307.1621B. doi:10.1126/science.1105776. PMID 15761153. S2CID 39457788.
• Lahuna O, Quellari M, Achard C, et al. (2005). "Thyrotropin receptor trafficking relies on the hScrib-betaPIX-GIT1-ARF6 pathway". EMBO J. 24 (7): 1364–74. doi:10.1038/sj.emboj.7600616. PMC 1142541. PMID 15775968.
• Navarro C, Nola S, Audebert S, et al. (2005). "Junctional recruitment of mammalian Scribble relies on E-cadherin engagement". Oncogene. 24 (27): 4330–9. doi:10.1038/sj.onc.1208632. PMID 15806148.
• Métais JY, Navarro C, Santoni MJ, et al. (2005). "hScrib interacts with ZO-2 at the cell-cell junctions of epithelial cells". FEBS Lett. 579 (17): 3725–30. doi:10.1016/j.febslet.2005.05.062. PMID 15975580. S2CID 4893407.
• Thomas M, Massimi P, Navarro C, et al. (2005). "The hScrib/Dlg apico-basal control complex is differentially targeted by HPV-16 and HPV-18 E6 proteins". Oncogene. 24 (41): 6222–30. doi:10.1038/sj.onc.1208757. PMID 16103886.