Beyond Cytokinesis: the Emerging Roles of CEP55 in Tumorigenesis
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Oncogene (2016) 35, 683–690 © 2016 Macmillan Publishers Limited All rights reserved 0950-9232/16 www.nature.com/onc REVIEW Beyond cytokinesis: the emerging roles of CEP55 in tumorigenesis J Jeffery1, D Sinha1,2, S Srihari3, M Kalimutho1 and KK Khanna1 CEP55 was initially identified as a pivotal component of abscission, the final stage of cytokinesis, serving to regulate the physical separation of two daughter cells. Over the past 10 years, several studies have illuminated additional roles for CEP55 including regulating the PI3K/AKT pathway and midbody fate. Concurrently, CEP55 has been studied in the context of cancers including those of the breast, lung, colon and liver. CEP55 overexpression has been found to significantly correlate with tumor stage, aggressiveness, metastasis and poor prognosis across multiple tumor types and therefore has been included as part of several prognostic ‘gene signatures’ for cancer. Here by discussing in depth the functions of CEP55 across different effector pathways, and also its roles as a biomarker and driver of tumorigenesis, we assemble an exhaustive review, thus commemorating a decade of research on CEP55. Oncogene (2016) 35, 683–690; doi:10.1038/onc.2015.128; published online 27 April 2015 INTRODUCTION CG-NAP and Pericentrin B.8 Like many other centrosomal A decade ago, we identified and characterized CEP55 (also proteins, CEP55 is a highly coiled-coil protein (Figures 1a).1 The known as c10orf3 and FLJ10540) as a centrosome-and midbody- N-terminus contains a homodimerization domain, while a hinge associated protein and a key regulator of cytokinesis.1 Subsequent region in the coiled coil has been termed the ESCRT and ALIX- studies described how CEP55 might cooperate with members of binding region (EABR) and is critical to its role in cytokinesis endosomal sorting complex required for transport (ESCRT) (Figures 1a and b).4,9 The C-terminus of the protein targets it to 2–4 machinery to constrict intracellular bridge to allow abscission. both the centrosome and the midbody.1 CEP55 not only localizes More recently, we and others have deciphered additional roles for primarily to the pericentriolar matrix but also is associated with CEP55 in regulating the PI3K/AKT pathway and stemness as well the mother centriole. It does not require the microtubules for its as in promoting tumorigenesis. Together, these studies have centrosomal localization. CEP55 interacts with the pericentriolar fi unveiled critical functions of CEP55 outside cytokinesis, rede ning matrix proteins CG-NAP and pericentrin B but is not required the paradigm of CEP55 action in cells. Herein, the pleiotropic roles for microtubule nucleation in interphase cells or for the of CEP55 including its function in cytokinesis and the implications localization of CG-NAP or pericentrin B to the centrosome.1,9 for human tumorigenesis are comprehensively discussed. CEP55 remains on the centrosome throughout the cell cycle and is recruited to the mitotic spindle during mitosis.9 Consistent fi CEP55 IN CYTOKINESIS with this, CEP55 has been identi ed in the human mitotic spindle proteome.10 CEP55 also localizes to the central spindle during fi Cytokinesis is the nal stage of cell division that divides the anaphase and the midbody during cytokinesis.1,11 CEP55 is cytoplasm equally amongst two daughter cells. After the DNA is reported to have microtubule-bundling activity in vitro,11 separated at opposite ends of the cell, the plasma membrane fi 5 although the signi canceofthisiscurrentlyunclear. begins to ingress in the middle where the midbody forms. During The localization of CEP55 to the central spindle and midbody is cytokinesis there is a sequential recruitment of protein complexes mediated through an interaction with the centralspindlin to the midbody, resulting in a cytokinetic bridge constricting on complex (comprised of MKLP1 and MgcRacGAP) by direct either side of the midbody and the severing of microtubules contact with MKLP1.11 The importance of this association was contained within the bridge. During abscission, the final stage of cytokinesis, the cytokinetic bridge tears at the constriction site, highlighted in MKLP1-depleted cells, where CEP55 could not thus providing physical separation between the daughter cells.6 localize to the midbody. The breast and ovarian cancer We initially described CEP55 as a centrosome- and midbody- susceptibility gene, BRCA2, was also recently shown to modulate 12 associated protein of ~ 55 kDa in size, which spans 464 amino recruitment of CEP55 to the midbody. Syntaxin16, a protein acids (Figure 1a).1 The centrosome is comprised of two centrioles involved in membrane fusion, has been shown to regulate surrounded by a cloud of electron-dense material known as the cytokinesis through its indispensable role in the recruitment of pericentriolar matrix.7 The pericentriolar matrix is comprised of recycling endosomes, exocyst components and CEP55 to the a number of coiled-coil proteins including key structural proteins midbody.13 1Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; 2School of Natural Sciences, Griffith University, Brisbane, Queensland, Australia and 3Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. Correspondence: Professor KK Khanna, Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, Queensland, Australia. E-mail: [email protected] Received 25 February 2015; revised 16 March 2015; accepted 16 March 2015; published online 27 April 2015 CEP55 and cancer J Jeffery et al 684 Figure 1. The role of CEP55 in cytokinesis. (a) Diagramatic representation of CEP55 and its domains. A coiled coil spans most of the protein, with a hinge region containing the ESCRT and ALIX-binding region (EABR). The N-terminal coiled-coil region (CC1) contains a homodimerization region (white dotted region), while the C-terminus (colored blue) targets CEP55 to the centrosome and midbody. This region is phosphorylated on S425, S428 and S436 during mitosis (red circles). (b) The structure of CEP55 complexes at the midbody. Each CEP55 homodimer can bind one molecule of either ALIX or TSG101 via its EABR domain. ALIX can then recruit ESCRT-III complexes directly, whereas TSG101 recruits ESCRT-III complexes via the recruitment of ESCRT-1. (c) The recruitment of ESCRT-III complexes in a CEP55-dependent manner promotes the formation of 17nm ESCRT-III filaments (pink), which creates a constriction site. ESCRT-III complexes then recruit Spastin to cleave the microtubules (orange). CEP55 recruits downstream machinery to the midbody Recently, BRCA2 has been reported to promote the ability of CEP55 is critical for correct midbody assembly and CEP55- CEP55 to recruit TSG101 and ALIX to the midbody independent of 12 depleted cells display an abnormal midbody structure with no its function in DNA repair, although the involvement of BRCA2 in 16 midbody visible under light microscopy.11 CEP55 targets cytokinesis remains controversial. Similarly, it is contentious a number of structural and regulatory proteins required for whether CEP55 has a more universal role in the regulation of completion of cytokinesis to the midbody including Aurora B, cytokinesis in mammalian cells as human embryonic kidney cells 14 MKLP2, PRC1, ECT2, Anillin and Syntaxin 2,11 demonstrating that (HEK293) continue to divide following CEP55 depletion. Addi- CEP55 is indispensable for midbody structure maintenance. tional work is required to discern whether this role is direct CEP55 also orchestrates final stage of abscission. During (by facilitating the actual abscission process) or indirect abscission, CEP55 at midbody recruits proteins that are directly (by regulating the recruitment of proteins involved in vesicular involved in the membrane fission (Tumor-susceptibility gene 101 trafficking). (TSG101) and ALG2-interacting protein X (ALIX)) and fusion events (Endobrevin) (Figures 1b and c).2,14 Centriolin, another centroso- The structure of CEP55/ESCRT complexes at the midbody mal protein, also recruits fission and fusion proteins by a distinct CEP55 complex formation with ALIX and TSG101 is required to 11,15 but parallel pathway. TSG101 is a component of ESCRT-I, while allow recruitment of ESCRT complexes to the midbody, which ALIX is an ESCRT-III associated protein.2 Both TSG101 and ALIX facilitate the membrane fission events necessary to create localize to centrosomes and have well-described functions in separation of the two daughter cells.2,14 Although there are retroviral budding as well as the membrane fission events of multiple ESCRT complexes (known as 0, I, II and III), ESCRT-III is the cytokinesis.2,14 Depletion of TSG101 or ALIX results in defective most critical for cytokinesis, forming long filamentous structures cytokinesis, which is reminiscent of the phenotype observed in which create the constriction site.2,14,17 ALIX is able to recruit CEP55-depleted cells with an increased proportion of multi- ESCRT-III directly, whereas TSG101 recruits ESCRT-I, which in turn nucleated cells and/or cells arrested at midbody stage.2 Notably, recruits ESCRT-III (Figure 1b).2,14 unlike TSG101 and ALIX viral budding is unaffected by depletion CEP55 is a highly coiled-coil protein which homodimerizes.9 of CEP55, indicating that CEP55 might act as an adaptor rather Initially, CEP55 was proposed to comprise of two coiled-coil than a component of the core ESCRT pathway to promote regions joined by a hinge