The Unique-5 and -6 Motifs of ZO-1 Regulate Tight Junction Strand Localization and Scaffolding Properties

The proper cellular location and sealing of tight junctions is assumed to depend on scaffolding properties of ZO-1, a member of the MAGUK protein family. ZO-1 contains a conserved SH3-GUK module that is separated by a variable region (unique-5), which in other MAGUKs has proven regulatory functions. To identify motifs in ZO-1 critical for its putative scaffolding functions, we focused on the SH3-GUK module including unique-5 (U5) and unique-6 (U6), a motif immediately C-terminal of the GUK domain. In vitro binding studies reveal U5 is sufficient for occludin binding; U6 reduces the affinity of this binding. In cultured cells, U5 is required for targeting ZO-1 to tight junctions and removal of U6 results in ectopically displaced junction strands containing the modified ZO-1, occludin, and claudin on the lateral cell membrane. These results provide evidence that ZO-1 can control the location of tight junction transmembrane proteins and reveals complex protein binding and targeting signals within its SH3-U5-GUK-U6 region. We review these findings in the context of regulated scaffolding functions of other MAGUK protein

MyD88 signalling in colonic mononuclear phagocytes drives colitis in IL-10-deficient mice

Commensal bacterial sensing by Toll-like receptors is critical for maintaining intestinal homeostasis, but can lead to colitis in the absence of interleukin-10. Although Toll-like receptors are expressed in multiple cell types in the colon, the cell type(s) responsible for the development of colitis are currently unknown. Here we generated mice that are selectively deficient in MyD88 in various cellular compartments in an interleukin-10[superscript −/−] setting. Although epithelial expression of MyD88 was dispensable, MyD88 expression in the mononuclear phagocyte compartment was required for colitis development. Specifically, phenotypically distinct populations of colonic mononuclear phagocytes expressed high levels of interleukin-1β, interleukin-23 and interleukin-6, and promoted T-helper 17 responses in the absence of interleukin-10. Thus, gut bacterial sensing through MyD88 in mononuclear phagocytes drives inflammatory bowel disease when unopposed by interleukin-10.Howard Hughes Medical InstituteNational Institutes of Health (U.S.) (NIH grant DK071754)National Institutes of Health (U.S.) (NIH grant AI046688)National Institutes of Health (U.S.) (NIH grant AI055502)National Institutes of Health (U.S.) (NIH grant RO1OD011141)National Institutes of Health (U.S.) (Training grant)National Cancer Institute (U.S.) (Irvington Fellowship

A PDZ-Binding Motif Controls Basolateral Targeting of Syndecan-1 Along the Biosynthetic Pathway in Polarized Epithelial Cells

The cell surface proteoglycan, syndecan-1, is essential for normal epithelial morphology and function. Syndecan-1 is selectively localized to the basolateral domain of polarized epithelial cells and interacts with cytosolic PDZ (PSD-95, discs large, ZO-1) domain-containing proteins. Here, we show that the polarity of syndecan-1 is determined by its type II PDZ-binding motif. Mutations within the PDZ-binding motif lead to the mislocalization of syndecan-1 to the apical surface. In contrast to previous examples, however, PDZ-binding motif-dependent polarity is not determined by retention at the basolateral surface but rather by polarized sorting prior to syndecan-1’s arrival at the plasma membrane. Although none of the four known PDZ-binding partners of syndecan-1 appears to control basolateral localization, our results show that the PDZ-binding motif of syndecan-1 is decoded along the biosynthetic pathway establishing a potential role for PDZ-mediated interactions in polarized sorting

Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas arising from an intraductal papillary mucinous neoplasm

Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells is a rare pancreatic tumor of unclear origin. This case reports a 72-year-old male with bloating and indigestion for about six years who was found to have a 5 cm laterally spreading ampullary mass and a 1.3 cm solid and cystic distal pancreas body mass on esophagogastroduodenoscopy (EGD) and endoscopic ultrasound (EUS). Histological examination of the pancreatic mass showed an undifferentiated carcinoma with osteoclast-like giant cells, contiguous with and apparently arising from an IPMN. Rare areas of glandular morphology within the invasive carcinoma, as well as patchy expression of epithelial markers and close physical association with an IPMN, clearly support an epithelial origin of this neoplasm and also suggest neoplastic progression from a preneoplastic ductal lesion to an invasive carcinoma, similar to the histogenesis of ductal-type pancreatic adenocarcinoma. Molecular analysis of the invasive carcinoma revealed mutations typical of pancreatic ductal carcinoma. Identical mutations were then identified within the intraductal mucinous neoplasm, consistent with origin of this rare pancreatic carcinoma subtype from IPMN. Keywords: UC-OGC, IPMN, Pancreas, K-ras, Neoplas