The Scribble family in cancer: twentieth anniversary

Santoni, Marie-Josée; Kashyap, Rudra; Camoin, Luc; Borg, Jean-Paul

doi:10.1038/s41388-020-01478-7

Cited by 44 publications

(48 citation statements)

References 130 publications

(244 reference statements)

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“…The Scribble protein is a highly conserved cell polarity regulator comprising 16 Leucine-Rich Repeats and four PSD-95/Discs-large/ZO-1 (PDZ) domains and belongs to the LAP family of proteins [ 6 , 7 ]. Together with Discs Large (Dlg) and Lethal Giant Larvae (Lgl), Scribble acts to establish and maintain tissue homeostasis, as well as directed cell migration and tissue growth [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Structural basis of the human Scribble–Vangl2 association in health and disease

How

Stephens

Lim

et al. 2021

Biochemical Journal

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Scribble is a critical cell polarity regulator that has been shown to work as either an oncogene or tumor suppressor in a context dependent manner, and also impacts cell migration, tissue architecture and immunity. Mutations in Scribble lead to neural tube defects in mice and humans, which has been attributed to a loss of interaction with the planar cell polarity regulator Vangl2. We show that the Scribble PDZ domains 1, 2 and 3 are able to interact with the C-terminal PDZ binding motif of Vangl2 and have now determined crystal structures of these Scribble PDZ domains bound to the Vangl2 peptide. Mapping of mammalian neural tube defect mutations reveal that mutations located distal to the canonical PDZ domain ligand binding groove can not only ablate binding to Vangl2 but also disrupt binding to multiple other signaling regulators. Our findings suggest that PDZ-associated neural tube defect mutations in Scribble may not simply act in a Vangl2 dependent manner but as broad-spectrum loss of function mutants by disrupting the global Scribble-mediated interaction network.

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Section: Introductionmentioning

confidence: 99%

Structural basis of the human Scribble–Vangl2 association in health and disease

How

Stephens

Lim

et al. 2021

Biochemical Journal

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“…However, when considering certain determinants of the PDZ protein such as basolateral expression in epithelial cells, expression in the thyroid follicular cell, and class 1 PDZ‐binding motif recognition, one major candidate partner was identified, the PDZ protein SCRIB. SCRIB is a basolateral membrane‐associated PDZ multidomain scaffold protein containing 4 carboxy‐terminal PDZ domains involved in PDZ‐mediated protein–protein interactions 30 . SCRIB PDZ domains typically bind carboxy‐terminal class 1 PDZ‐binding motifs, and exhibit overlapping specificities for particular ligands, with each PDZ domain able to bind multiple interaction partners 31 .…”

Section: Resultsmentioning

confidence: 99%

“…SCRIB is a basolateral membrane-associated PDZ multidomain scaffold protein containing 4 carboxy-terminal PDZ domains involved in PDZ-mediated protein-protein interactions. 30 SCRIB PDZ domains typically bind carboxy-terminal class 1 PDZ-binding motifs, and exhibit overlapping specificities for particular ligands, with each PDZ domain able to bind multiple interaction partners. 31 Interestingly, PDZ Domain Arrays revealed that only SCRIB PDZ domains 1 and 4 strongly interact with NIS carboxy-terminus.…”

Section: The Pdz Protein Scrib Stabilizes Nis Expression At the Plasmmentioning

confidence: 99%

The PDZ protein SCRIB regulates sodium/iodide symporter (NIS) expression at the basolateral plasma membrane

et al. 2021

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The sodium/iodide symporter (NIS) expresses at the basolateral plasma membrane of the thyroid follicular cell and mediates iodide accumulation required for normal thyroid hormonogenesis. Loss-of-function NIS variants cause congenital hypothyroidism due to impaired iodide accumulation in thyroid follicular cells underscoring the significance of NIS for thyroid physiology. Here we report novel findings derived from the thorough characterization of the nonsense NIS mutant p.R636* NIS-leading to a truncated protein missing the last eight amino acids-identified in twins with congenital hypothyroidism. R636* NIS is severely mislocalized into intracellular vesicular compartments due to the lack of a conserved carboxy-terminal type 1 PDZ-binding motif. As a result, R636* NIS is barely targeted to the plasma membrane and therefore iodide transport is reduced. Deletion of the PDZ-binding motif causes NIS accumulation into late endosomes and lysosomes. Using PDZ domain arrays, we revealed that the PDZ-domain containing protein SCRIB binds to the carboxy-terminus of NIS by a PDZ-PDZ interaction. Furthermore, in CRISPR/Cas9based SCRIB deficient cells, NIS expression at the basolateral plasma membrane is compromised, leading to NIS localization into intracellular vesicular compartments.We conclude that the PDZ-binding motif is a plasma membrane retention signal that participates in the polarized expression of NIS by selectively interacting with the PDZ-domain containing protein SCRIB, thus retaining the transporter at the basolateral plasma membrane. Our data provide insights into the molecular mechanisms that regulate NIS expression at the plasma membrane, a topic of great interest in the 2 of 13 | MARTÍN eT Al.

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“…Together, these results suggest that subcellular localization of SCRIB, especially in nuclei and cytoplasm, might be important in the tumorigenic role of SCRIB, which warrants additional study. Loss of cell polarity protein might serve to induce tumors by promoting the uncontrolled proliferation of cells [28,29]. Therefore, as a component of polarity protein, SCRIB has been suggested as a tumor suppressor, and loss of SCRIB induced tumorigenesis in MYC-induced transformed epithelial cells [6].…”

Section: Discussionmentioning

confidence: 99%

SCRIB Is Involved in the Progression of Ovarian Carcinomas in Association with the Factors Linked to Epithelial-to-Mesenchymal Transition and Predicts Shorter Survival of Diagnosed Patients

et al. 2021

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SCRIB is a polarity protein important in maintaining cell junctions. However, recent reports have raised the possibility that SCRIB might have a role in human cancers. Thus, this study evaluated the roles of SCRIB in ovarian cancers. In 102 human ovarian carcinomas, nuclear expression of SCRIB predicted shorter survival of ovarian carcinoma patients, especially in the patients who received post-operative chemotherapy. In SKOV3 and SNU119 ovarian cancer cells, overexpression of SCRIB stimulated the proliferation and invasion of cells. Knockout of SCRIB inhibited in vivo tumor growth of SKOV3 cells and overexpression of SCRIB promoted tumor growth. Overexpression of SCRIB stimulated epithelial-to-mesenchymal transition by increasing the expression of N-cadherin, snail, TGF-β1, and smad2/3, and decreasing the expression of E-cadherin; the converse was observed with inhibition of SCRIB. In conclusion, this study presents the nuclear expression of SCRIB as a prognostic marker of ovarian carcinomas and suggests that SCRIB is involved in the progression of ovarian carcinomas by stimulating proliferation and epithelial-to-mesenchymal transition-related invasiveness.

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The Scribble family in cancer: twentieth anniversary

Cited by 44 publications

References 130 publications

Structural basis of the human Scribble–Vangl2 association in health and disease

Structural basis of the human Scribble–Vangl2 association in health and disease

The PDZ protein SCRIB regulates sodium/iodide symporter (NIS) expression at the basolateral plasma membrane

SCRIB Is Involved in the Progression of Ovarian Carcinomas in Association with the Factors Linked to Epithelial-to-Mesenchymal Transition and Predicts Shorter Survival of Diagnosed Patients

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