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TACC-Ling Microtubule Dynamics and Centrosome Function

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TACC-Ling Microtubule Dynamics and Centrosome Function Review The TACC proteins: TACC-ling microtubule dynamics and centrosome function Isabel Peset1 and Isabelle Vernos1,2 1 Cell and Developmental Biology Program, Centre for Genomic Regulation (CRG), University Pompeu Fabra (UPF), Dr Aiguader 88, Barcelona 08003, Spain 2 Institucio´ Catalana de Recerca i Estudis Avanc¸ats (ICREA), Passeig Lluis Companys 23, 08010 Barcelona, Spain A major quest in cell biology is to understand the Transforming acidic coiled-coil (TACC) proteins emerged molecular mechanisms underlying the high plasticity initially as a group of proteins implicated in cancer. The of the microtubule network at different stages of the first member of the TACC family to be discovered was cell cycle, and during and after differentiation. Initial identified in a search of genomic regions that are amplified reports described the centrosomal localization of in breast cancer. It was named transforming acidic coiled- proteins possessing transforming acidic coiled-coil coil 1 (TACC1) because of its highly acidic nature, the (TACC) domains. This discovery prompted several presence of a predicted coiled-coil domain at its C terminus groups to examine the role of TACC proteins during cell (now known as the TACC domain), and its ability to division, leading to indications that they are important promote cellular transformation [6]. TACC proteins are players in this complex process in different organisms. present in different organisms, ranging from yeasts to Here, we review the current understanding of the role of mammals. There is only one TACC protein in the nema- TACC proteins in the regulation of microtubule tode Caenorhabditis elegans (TAC-1), in Drosophila mel- dynamics, and we highlight the complexity of centro- anogaster (D-TACC), in Xenopus laevis (Maskin), and some function. Introduction Cell proliferation and differentiation require dramatic Abbreviations rearrangements of the cytoskeleton that rely on the highly AINT: ARNT interacting protein dynamic nature of the cytoskeletal components. Microtu- AKAP350: A kinase (PRKA) anchor protein bules are dynamic filaments with fundamental roles in Alp7: Altered growth polarity 7 eukaryotic cell organization and function. During cell Ark1: aurora-related kinase ARNT: aryl hydrocarbon nuclear translocator protein division, they form the bipolar spindle, which segregates AZU-1: anti-zuai-1 the chromosomes into the two daughter cells. Microtubules CBP: calcium-binding protein show prolonged states of polymerization and depolymer- CPEB: cytoplasmic polyadenylation element binding protein ization that interconvert stochastically, exhibiting fre- DCLK: doublecortin-like kinase quent transitions between growing and shrinking ECTACC: endothelial cell TACC E1F4E: eukaryotic initiation factor 4E phases, a property called ‘dynamic instability’ [1]. In the ERIC: erythropoietin-induced cDNA cell, multiple factors modulate this property by acting FOG-1: Friend of Gatal positively or negatively on the nucleation, elongation or GAS41: glioma amplified sequence 41 destabilization of microtubules [1–3]. The relative activity GCN5L2: general control of amino-acid synthesis 5-like 2 g-TURC: g-tubulin related complex of all these factors determines the steady-state length and HEAT: huntingtin, elongation factor 3, A subunit of protein stability of microtubules, in addition to their organization, phosphatase 2A and TOR1 and it is largely dictated by global and local phosphoryl- INI-1: SWI/SNF core subunit ation–dephosphorylation reactions [2,3]. In addition, other Ipl1: Increase-in-ploidy 1 types of factors that have microtubule-severing and - ISREC: Swiss Institute for Experimental Cancer Research KIF2C: kinesin family member 2C anchoring activities also influence the microtubule net- LIS1: Lissencephaly-1 work. The main microtubule-organizing centre (MTOC) LSM7: U6 small nuclear NRA associated of animal cells, the centrosome, acts as a platform upon MBD2: methyl-CpG binding domain protein 2 which the different factors and activities accumulate in a Mial: melanoma inhibitory activity 1 regulated manner. It therefore exerts a tight local and Mps1: MonoPolar Spindle 1 NDEL1 and NUDEL: nude nuclear distribution gene E homolog temporal control on the number, distribution and polarity (A. nidulans)-like 1 pCAF, p300/CBP-associated factor of microtubules [4,5]. SmG: snRNP Sm protein G TTK: TTK protein kinase Zyg-8: ZYGote defective Corresponding authors: Peset, I. ([email protected]); Zyg-9: ZYGote defective Vernos, I. ([email protected]). 0962-8924/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tcb.2008.06.005 Available online 23 July 2008 379 Review Trends in Cell Biology Vol.18 No.8 in the fission yeast Schizosaccharomyces pombe (Alp7 Although TACC1 was originally found to be upregulated also known as Mia1p); by contrast, mammals have three in breast cancer [6], subsequent studies found that its such proteins (TACC1, TACC2 [also known as AZU-1 and expression is reduced in ovarian and breast cancer tissues ECTACC] and TACC3 [also known as AINT and ERIC1]) [18,19]. TACC3 is also upregulated in several cancer cell [7–11]. Alternative splicing further increases the comp- lines, including lung cancer [17,20]; but, again, it was lexity of the TACC protein family in mammals and flies reported as being absent or reduced in ovarian and thyroid [12–16]. cancer tissues [21]. Initially, it was suggested that the The three human genes encoding TACC proteins are all TACC2 splice variant AZU-1 is a tumor suppressor in in genomic regions that are rearranged in certain cancers, breast cancer. However, the lack of any tumor phenotype and their expression is altered in cancers from different in Tacc2-knockout mice did not support this idea [22].It tissues. TACC1 and TACC2 are located in chromosomes therefore appears that these proteins can be upregulated 8p11 and 10q26, respectively, two regions that are impli- or downregulated in different types of cancer or, surpris- cated in breast cancer and other tumors [6], and TACC3 ingly, even in the same type [14,18–25]; as such, their maps to 4p16, within a translocation breakpoint region putative involvement in cancer development and/or pro- associated with the disease multiple myeloma [17]. gression is unclear. Figure 1. The TACC family of proteins: structural organization and regions of interaction with binding partners. The figure shows alignment of the key structural features, and the position of domains that interact with binding partners (underlined regions). TACC proteins have the conserved coiled-coil TACC domain at their C terminus (blue box). In addition, some members have highly acidic, imperfect repeats of 33 amino acids (termed SPD repeats [28] owing to their specific amino acid composition [pale-blue boxes]) or a Ser–Pro Azu-1 motif (SPAZ) [24] (dark-grey boxes). Yellow lines indicate the position of nuclear localization signals (NLSs). The conserved consensus sequences for AurA phosphorylation are shown as orange bars. The conserved Ser residue is highlighted in orange, and additional consensus sites in Maskin are indicated in grey. The position of the Leu residue, which is important for the C. elegans TAC-1–Zyg-9 interaction, is shown with a white line [44]. For the sake of simplicity, only TACC family proteins that have mapped interactions are shown. 380 Review Trends in Cell Biology Vol.18 No.8 Almost at the same time as the identification of the role of TACC proteins at the centrosome, and we TACC1 in humans, Maskin was identified and extensively discuss some of the issues that still remain to be addressed. characterized as a factor involved in the regulation of mRNA translation during maturation of Xenopus oocytes The TACC proteins [26]. Other TACC family members have also been impli- The TACC domain is the signature of this protein family. cated in various events related to gene regulation, in- This coiled-coil domain is found at the C terminus of all cluding the regulation of translation, RNA maturation the family members, which have otherwise very diverse and gene expression (Figure 1, Table 1) [13,25,27–31]. N-terminal domains (Figure 1) [7,16]. The TACC domain However, to date, no major common role has emerged shows a high level of conservation throughout evolution, for TACC proteins in these processes. By contrast, a major and the shorter member of the family, C. elegans TAC-1, breakthrough came with the identification of D-TACC as a consists of basically one TACC domain [8–10]. Together, Drosophila microtubule-associated and centrosomal this suggests that the TACC domain carries most of protein required for centrosome activity and microtubule the common functional properties of this family of assembly during mitosis [12]. Since then, the idea that proteins. TACC proteins have a role in regulating microtubule The temporal and tissue-specific expression patterns of assembly has gained solid support through various studies the three mammalian TACC proteins have been more performed in different experimental systems. In the light extensively studied. TACC1 can be detected in several of these data, we review here our current understanding of adult tissues, but relatively high levels of expression occur Table 1. Partners of TACC proteins, and the putative functions of their interactions The table summarizes all the interreactions described in the literature for some TACC proteins. Proteins involved in MT dynamics and centrosomal functions are indicated in red; proteins involved in RNA regulation are indicated in green; proteins
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