SCRIB

SCRIB, also known as Scribble, SCRIBL, or Scribbled homolog (Drosophila), is a scaffold protein which in humans is encoded by the SCRIB gene.[5][6] 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.[7] In humans, SCRIB is found as a membrane protein and is involved in cell migration, cell polarity, and cell proliferation in epithelial cells.[7][8] There is also strong evidence that SCRIB may play a role in cancer progression because of its strong homology to the Drosophila protein.[7]

SCRIB
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSCRIB, CRIB1, SCRB1, SCRIB1, Vartul, scribbled planar cell polarity protein, scribble planar cell polarity protein, oSCRIB
External IDsOMIM: 607733 MGI: 2145950 HomoloGene: 44228 GeneCards: SCRIB
Orthologs
SpeciesHumanMouse
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 MbChr 15: 75.92 – 75.94 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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.[8]

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.[9] 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.[7] 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.[9] 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.[7]

Structure

The human homolog is a LAP protein, it contains 16 leucine-rich repeats and four PDZ domains.[10] 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.[11]

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.[9] SCRIB is also found in cellular junctions such as adherens junctions and tight junctions.[12] Specifically, it is located in the kidney, skeletal muscles, liver, lung, breast, intestine, placenta and epithelial cells.[13]

Clinical significance

The PDZ domain of SCRIB binds directly to the human papillomavirus E6 protein.[14] SCRIB is targeted for ubiquitination by a complex of E6 and UBE3A and E6 induces degradation of SCRIB.[14]

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).[7] Specifically, SCRIB deficient mutants have been shown to promote the activity of numerous oncogenes.[9] 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.[9][15] 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.[16]

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.[17]

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.[18] 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.[17]

References
  1. ENSG00000180900 GRCh38: Ensembl release 89: ENSG00000274287, ENSG00000180900 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000022568 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: SCRIB scribbled homolog (Drosophila)".
  6. Nagase T, Seki N, Tanaka A, Ishikawa K, Nomura N (August 1995). "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.
  7. Patrick Humbert; Sarah Russell; Helena Richardson (June 2003). "Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer". BioEssays. 25 (6): 542–53. doi:10.1002/bies.10286. PMID 12766944.
  8. L E Dow; J S Kauffman; J Caddy; A S Peterson; S M Jane; S M Russell & P O Humbert (April 2007). "The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge". Oncogene. 26 (16): 2272–82. doi:10.1038/sj.onc.1210016. PMID 17043654.
  9. Royer C, Lu X (September 2011). "Epithelial cell polarity: a major gatekeeper against cancer?". Cell Death Differ. 18 (9): 1470–7. doi:10.1038/cdd.2011.60. PMC 3178423. PMID 21617693.
  10. Jennifer N. Murdoch; Deborah J. Henderson; Kit Doudney; Carles Gaston-Massuet; Helen M. Phillips; Caroline Paternotte; Ruth Arkell; Philip Stanier & Andrew J. Copp (November 2002). "Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse". Hum. Mol. Genet. 12 (2): 87–98. doi:10.1093/hmg/12.2.87. PMID 12499390.
  11. 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 (November 2008). "Scrib regulates PAK activity during the cell migration process". Hum. Mol. Genet. 17 (22): 3552–65. doi:10.1093/hmg/ddn248. PMID 18716323.
  12. Petit MM, Meulemans SM, Alen P, Ayoubi TA, Jansen E, Van de Ven WJ (January 2005). "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.
  13. Navarro C, Nola S, Audebert S, Santoni MJ, Arsanto JP, Ginestier C, Marchetto S, Jacquemier J, Isnardon D, Le Bivic A, Birnbaum D, Borg JP (June 2005). "Junctional recruitment of mammalian Scribble relies on E-cadherin engagement". Oncogene. 24 (27): 4330–9. doi:10.1038/sj.onc.1208632. PMID 15806148.
  14. Nakagawa S, Huibregtse JM (November 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.
  15. Zhan L, Rosenberg A, Bergami KC, Yu M, Xuan Z, Jaffe AB, Allred C, Muthuswamy SK (November 2008). "Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma". Cell. 135 (5): 865–78. doi:10.1016/j.cell.2008.09.045. PMC 3015046. PMID 19041750.
  16. L E Dow; I A Elsum; C L King; K M Kinross; H E Richardson & P O Humbert (July 2008). "Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling". Oncogene. 27 (46): 5988–6001. doi:10.1038/onc.2008.219. PMID 18641685.
  17. Valentina Vaira; Alice Faversani; Takehiko Dohi; Marco Maggioni; Mario Nosotti; Delfina Tosi; Dario C Altieri; Silvano Bosari (June 2011). "Aberrant Overexpression of the Cell Polarity Module Scribble in Human Cancer". The American Journal of Pathology. 178 (6): 2478–83. doi:10.1016/j.ajpath.2011.02.028. PMC 3124121. PMID 21549346.
  18. Yi Qin; Christopher Capaldo; Barry M. Gumbiner & Ian G. Macara (December 2005). "The mammalian SCRIB polarity protein regulates epithelial cell adhesion and migration through E-cadherin". Journal of Cell Biology. 171 (6): 1061–71. doi:10.1083/jcb.200506094. PMC 2171311. PMID 16344308.

Further reading
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