RESEARCH HIGHLIGHTS Nature Reviews Cancer | AOP, published online 10 January 2013; doi:10.1038/nrc3453 POLARITY Merlin and ezrin get organized The ezrin, radixin and moesin (ERM) proteins and the closely related tumour suppressor neuro­ fibromatosis type 2 (NF2; also known as merlin) function as scaffolds to organize the cell cortex localization and to help regulate cell polarity of ezrin all during epithelial morphogenesis, around the cell cortex. a process that is often disrupted in Therefore, NF2 seems to tumorigenesis. However, how NF2 be involved in restricting the and the ERM proteins achieve this localization of ezrin, a process organization, and the functional that the authors found requires relationship among these proteins, is α-catenin; this is interesting as it not completely clear. indicates a junction-independent Andrea McClatchey and col­ function for α-catenin. leagues followed the localization of Given the connections of the ezrin and NF2 during the establish­ ezrin cap to the cell cycle, the authors ment of apical–basal polarity in also examined the centrosomes and Lara Crow/NPG single Caco2 intestinal epithelial cells mitotic spindle position in single embedded in Matrigel. They noted Caco2 cells; they found that their (these mice eventually develop renal that ezrin became restricted into localization was tightly correlated carcinomas), and ectopic ezrin a cap-like structure at the plasma with the ezrin cap. Supporting this, localization and multi-layering in the membrane prior to the first cell centrosomes in cells expressing NF2 colon. In addition, cancer cells often division. The cells were uniformly shRNA were found near areas of have extra centrosomes; these can surrounded by extracellular matrix the cortex with ectopic ezrin, and be clustered to allow the cell to form and the cap lacked markers of apical spindles were aberrantly oriented in bipolar spindles, but loss of clustering polarity, indicating that intrinsic these cells. Through organized cell can lead to multipolar spindles and cues establish this ezrin localization division, Caco2 cells normally form aneuploidy. In several tumour cell prior to the formation of a true apical polarized cysts with single lumen, a lines expressing NF2 shRNA, as well surface. Furthermore, the ezrin cap process that requires correct spindle as NF2-deficient mesothelioma cells, began to form during G1 phase of the orientation. Cells lacking NF2 or loss of NF2 prevented centrosome cell cycle and was mostly completed α-catenin formed aberrant structures clustering and resulted in multipolar by S phase, and cap formation with multiple lumens, a phenotype spindle formation. Therefore, NF2 required the cyclin-dependent kinase that was previously observed in other may suppress tumours by restricting CDK5 (which can phosphorylate the models with misorientation of the ezrin localization to establish and NF2 seems to ezrin FERM domain), linking this mitotic spindle. maintain cell polarity and spindle be involved in event to the cell cycle. To determine the in vivo relevance orientation, and may also help In contrast to ezrin, NF2 did not of these findings, the authors exam­ prevent genomic instability. restricting the localize to the cap structure, but was ined three tissues in Nf2–/– mice. Sarah Seton-Rogers localization of found throughout the cell cortex. They found that Nf2–/– mice have ORIGINAL RESEARCH PAPER Hebert, A. M. et al. ezrin However, short hairpin RNA (shRNA) spindle orientation defects and Merlin/ERM proteins establish cortical asymmetry against NF2 prevented ezrin cap multi-layering in the skin, aberrant and centrosome position. Genes Dev. 26, formation, and resulted in ectopic centrosome localization in the kidney 2709–2723 (2012) NATURE REVIEWS | CANCER VOLUME 13 | FEBRUARY 2013 © 2013 Macmillan Publishers Limited. All rights reserved.