Biology:SCRIB

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SCRIB, also known as Scribble, SCRIBL, or Scribbled homolog (Drosophila), is a scaffold protein which in humans is encoded by the SCRIB gene.[1][2] 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.[3] In humans, SCRIB is found as a membrane protein and is involved in cell migration, cell polarity, and cell proliferation in epithelial cells.[3][4] There is also strong evidence that SCRIB may play a role in cancer progression because of its strong homology to the Drosophila protein.[3]

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.[4]

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.[5] 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.[3] 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.[5] 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.[3]

Structure

The human homolog is a LAP protein, it contains 16 leucine-rich repeats and four PDZ domains.[6] 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.[7]

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.[5] SCRIB is also found in cellular junctions such as adherens junctions and tight junctions.[8] Specifically, it is located in the kidney, skeletal muscles, liver, lung, breast, intestine, placenta and epithelial cells.[9]

Clinical significance

The PDZ domain of SCRIB binds directly to the human papillomavirus E6 protein.[10] SCRIB is targeted for ubiquitination by a complex of E6 and UBE3A and E6 induces degradation of SCRIB.[10]

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).[3] Specifically, SCRIB deficient mutants have been shown to promote the activity of numerous oncogenes.[5] 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.[5][11] 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.[12]

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.[13]

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.[14] 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.[13]

References

  1. ↑ "Entrez Gene: SCRIB scribbled homolog (Drosophila)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23513. 
  2. ↑ "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. August 1995. doi:10.1093/dnares/2.4.167. PMID 8590280. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 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. 
  4. ↑ 4.0 4.1 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. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "Epithelial cell polarity: a major gatekeeper against cancer?". Cell Death Differ. 18 (9): 1470–7. September 2011. doi:10.1038/cdd.2011.60. PMID 21617693. 
  6. ↑ Jennifer N. Murdoch; Deborah J. Henderson; Kit Doudney; Carles Gaston-Massuet; Helen M. Phillips; Caroline Paternotte; Ruth Arkell; Philip Stanier et al. (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. 
  7. ↑ "Scrib regulates PAK activity during the cell migration process". Hum. Mol. Genet. 17 (22): 3552–65. November 2008. doi:10.1093/hmg/ddn248. PMID 18716323. 
  8. ↑ "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. January 2005. doi:10.1186/1471-2121-6-1. PMID 15649318. 
  9. ↑ "Junctional recruitment of mammalian Scribble relies on E-cadherin engagement". Oncogene 24 (27): 4330–9. June 2005. doi:10.1038/sj.onc.1208632. PMID 15806148. 
  10. ↑ 10.0 10.1 "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. November 2000. doi:10.1128/MCB.20.21.8244-8253.2000. PMID 11027293. 
  11. ↑ "Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma". Cell 135 (5): 865–78. November 2008. doi:10.1016/j.cell.2008.09.045. PMID 19041750. 
  12. ↑ 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. 
  13. ↑ 13.0 13.1 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. PMID 21549346. 
  14. ↑ 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. PMID 16344308. 

Further reading




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