WW domain-mediated interaction with Wbp2 is important for the oncogenic property of TAZ

The transcriptional co-activators YAP and TAZ are downstream targets inhibited by the Hippo tumor suppressor pathway. YAP and TAZ both possess WW domains, which are important protein–protein interaction modules that mediate interaction with proline-rich motifs, most commonly PPXY. The WW domains of YAP have complex regulatory roles as exemplified by recent reports showing that they can positively or negatively influence YAP activity in a cell and context-specific manner. In this study, we show that the WW domain of TAZ is important for it to transform both MCF10A and NIH3T3 cells and to activate transcription of ITGB2 but not CTGF, as introducing point mutations into the WW domain of TAZ (WWm) abolished its transforming and transcription-promoting ability. Using a proteomic approach, we discovered potential regulatory proteins that interact with TAZ WW domain and identified Wbp2. The interaction of Wbp2 with TAZ is dependent on the WW domain of TAZ and the PPXY-containing C-terminal region of Wbp2. Knockdown of endogenous Wbp2 suppresses, whereas overexpression of Wbp2 enhances, TAZ-driven transformation. Forced interaction of WWm with Wbp2 by direct C-terminal fusion of full-length Wbp2 or its TAZ-interacting C-terminal domain restored the transforming and transcription-promoting ability of TAZ. These results suggest that the WW domain-mediated interaction with Wbp2 promotes the transforming ability of TAZ

A clinical and histopathologic focus on Barrett esophagus and Barrett-related dysplasia

Context.-Barrett esophagus is a metaplastic, premalignant lesion associated with approximately 0.5% annual incidence of progression to esophageal adenocarcinoma. Diagnosis and screening of Barrett esophagus and Barrett-related dysplasia relies on histologic evaluation of endoscopicmucosal biopsies, a process that is burdened with interobserver variability. Objectives.-To review the histologic features and classification of Barrett esophagus and Barrett-related dysplasia, to discuss the underlying difficulties in diagnosis and pitfalls, and to provide a brief review of new developments related to therapeutic modalities for patients diagnosed with dysplasia. Data Sources.-Sources include a review of relevant literature indexed in PubMed (US National Library of Medicine). Conclusions.-In spite of interobserver variability, histologic assessment of dysplasia is currently the accepted method of surveillance, and subsequent patient management is dictated by this evaluation. Although not universal, endoscopic therapy is increasingly important in replacing esophagectomy for patients with high-grade dysplasia or early carcinoma. (Arch Pathol Lab Med. 2011;135:1249-1260; doi: 10.5858/arpa.2011-0019-RA

Pathology and Genetics of Syndromic Gastric Polyps

Gastric polyps are found in 1% to 4% of patients undergoing gastroscopy. The vast majority are sporadic, but some gastric polyps indicate an underlying syndrome. Gastric polyps can manifest in each of the gastrointestinal polyposis syndromes, including the recently described gastric adenocarcinoma and proximal polyposis of the stomach syndrome. In addition, gastric polyps occur in Lynch syndrome and in a few rare conditions that are not primarily gastrointestinal. While some of these syndromes are clearly associated with an increased risk of gastric cancer, others are not. Interestingly, even in disorders with a well-established risk of gastric cancer, the neoplastic potential and the precursor status of these gastric polyps are not always clear. Although rare, recognition of syndromic gastric polyps is important for individual patient management. These conditions also serve as important models to study gastric homeostasis and gastric tumorigenesis

Some Morphology Frontiers of Dysplasia in the Tubular Gastrointestinal Tract The Rodger C. Haggitt Memorial Lecture

This review, based on the content of the 2020 US Gastrointestinal Pathology Society's Rodger Haggitt Lecture, concerns an array of tubular gastrointestinal tract dysplastic or possible "predysplastic lesions" with an almost purely morphologic focus based on our collaborative efforts over the past few years. These processes include esophageal epidermoid metaplasia, Barrett esophagus-associated dysplasia, polypoid gastric dysplastic lesions, small intestinal dysplasia, and the ability of metastases to mimic it, the controversial "serrated epithelial change" encountered in the setting of long-standing ulcerative and Crohn colitis, and recently described anal columnar human papilloma virus-associated neoplasms