Visit our Expo - Redox and Inflammation signaling 2012

The mammalian tumor suppressor Scribble has a key role in cell migration
Sébastien Nola, Marie-Josée Santoni, Claire Nourry, Christelle Navarro and Jean-Paul
Borg.
Molecular Pharmacology, Marseille Cancer Institute, UMR599 Inserm-Institut Paoli-
Calmettes, Marseille, France 13009. E-mail : borg@marseille.inserm.fr
Genetic studies in Drosophila and mice have shown that the PDZ protein Scribble has a
crucial role in many aspects of cell polarity. Loss of function of Scribble in Drosophila
provokes profound defects in epithelial apico-basal polarity, as well as the formation of
neoplastic tumors. Mice deficient for Scribble show abnormal planar cell polarity, and die
within a few days after birth from craniorachischisis, a dramatic neural tube defect. We have
shown that mammalian Scribble is a cytoplasmic protein tighly associated to the plasma
membrane, and that it is part of a protein complex containing betaPIX, an exchange factor for
Rac and Cdc42, and GIT1, a GTPase Activating Protein (GAP) for Arf6. The PDZ domains
of Scribble associate directly to the carboxy-terminus of betaPIX, and beta-PIX is bound to
GIT1. Here, we demonstrate that PAK, a serine-threonine kinase, is also associated to
Scribble in epithelial cells. The Scribble-betaPIX-GIT1-PAK protein complex is located at the
leading edge of migratory T47D epithelial cells, and, using siRNA and dominant-negative
constructs, we demonstrate that localization of betaPIX is dependant on the correct
positioning of Scribble at the plasma membrane. Using a modified Boyden chamber assay, we
show that Scribble, as well as the members of the associated protein complex, are required for
the effective migration of T47D cells towards a chemoattractant stimulus. In conclusion,
Scribble and the associated betaPIX-GIT1-PAK protein complex is required for cell migration
of epithelial cells. The unproper positioning of the betaPIX-GIT1-PAK signalling machinery
in Scribble deficient cells probably accounts for the cell migration defect in T47D cells and
may explain the neural tube defect observed in Scribble deficient mice.
Nourry C, Grant SG, Borg JP (2003). PDZ domain proteins: plug and play! Science’s STKE
179: RE7.
Legouis R, Jaulin-Bastard F, Schott S, Navarro C, Borg J-P, and Labouesse M (2003).
Basolateral targeting by Leucine Rich Repeat domains in epithelial cells. EMBO Reports 4:
1096–1100.
Audebert S., Navarro C., Nourry C., Chasserot-Golaz S., Lécine P., Bellaiche Y., Dupont J.-
L., Premont R.T., Sempéré C., Strub J.-M., Van Dorsselaer A., Vitale N. and Borg J.-P.
Mammalian Scribble forms a tight complex with the bPIX exchange factor (2004). Current
Biology 14: 987-95.
Navarro C., Nola S., Audebert S., Santoni M.-J., Arsanto J.-P., Ginestier C., Marchetto S.,
Jacquemier J., Isnardon D., Le Bivic A., Birnbaum D., and Borg J.-P. Junctional recruitment
of mammalian Scribble relies on E-cadherin engagement. (2005) Oncogene, 24: 4330-4339.
O.Lahuna*, Quellari M., Achard C., Nola S., Méduri G., Navarro C., Vitale N., Borg J.-P.*
and Misrahi M*. Thyrotropin receptor trafficking relies on the hScrib-bPIX-GIT1-ARF6
signaling pathway. (2005) The EMBO Journal, 24: 1364-1374. (*) co-corresponding authors.
Margolis B. and Borg J.-P. Apico-basal polarity complexes. J Cell Science, 118: 5157-5159.
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