American Society for Investigative Pathology, February 2010, Vol 2, No. 1

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Featuring articles recently published by ASIP Trainees in The American Journal of Pathology and The Journal of Molecular Diagnostics.

Tumor Suppressor Scribble Regulates Assembly of Tight Junctions in the Intestinal Epithelium
Ivanov AI, Young C, Beste KD, Capaldo CT, Humbert PO, Brennwald P, Parkos CA, Nusrat A.
Am J Pathol. 2010 Jan;176(1): p. 134-45

A synopsis written by co-author and ASIP trainee Dr. Christopter Capaldo at Emory University School of Medicine.

Cellular polarity is broadly defined as the ability of the cell to establish functionally distinct plasma membrane surfaces. The protein components involved in this nearly ubiquitous biological process, are shared between a startling array of organisms, cell types, and physiological circumstances. Indeed, these proteins provide a general spatial patterning role for the cell, and as such, are referred to as polarity proteins, or polarity complexes.

The cell polarity protein Scribble is one such component. In epithelial tissues, Scribble acts in concert with Disc-Large (Dlg) and Lethal Giant Larvae (Lgl) to define lateral membrane surfaces and contribute to the formation of intercellular tight junctions. Tight junctions are macro-molecular complexes that prevent the diffusion of plasma membrane lipids and proteins between apical and lateral domains, and hence, are important structures for maintaining epithelial cell polarity. Tight junctions also regulate the paracellular pathway by restricting the flux of molecules and solutes between cells. The Scribble complex interacts with the Par and Pals polarity complexes, in a mutually antagonistic fashion, to establish lateral and apical membrane domains respectively.

Recently, our laboratory observed Scribble at tight junctions in colonic epithelial cells. Using siRNA mediated suppression of Scribble, a correlation was discovered between Scribble levels and tight junction function, i.e., depletion of Scribble increased the “leakiness” of intestinal epithelia monolayers. We also discovered a novel interaction between Scibble and the tight junction scaffold protein ZO-1, which suggests a role for Scribble in maintaining tight junction integrity. Interestingly, treatment with proinflammatory cytokines displaced Scribble from the cell junctions and decreased its protein levels. Likewise, mucosal inflammation in vivo, as seen in colonic tissue samples from Crohn’s disease patients, correlated with decreased Scribble localization at tight junctions.

Our report shows that the polarity protein Scribble acts to enhance epithelial barrier properties through the maintenance of tight junction structures. Two salient facts put these findings in the context of disease pathogenesis. First, our group and others have shown that tight junction barrier dsyfunction is associated with inflammatory bowel disease, which involves pathologic mucosal inflammation. Secondly, Scribble is a tumor suppressor, as evidenced by the human papilloma tumor virus (HPV). HPV targets Scribble for proteolysis and is the agent responsible for cervical cancer. Therefore, our findings contribute to growing body of evidence linking tight junction barrier dysfunction with heightened inflammation and increased risk of carcinogenesis.