The TACC proteins: TACC-ling microtubule dynamics and centrosome function

A major quest in cell biology is to understand the molecular mechanisms underlying the high plasticity of the microtubule network at different stages of the cell cycle, and during and after differentiation. Initial reports described the centrosomal localization of proteins possessing transforming acidic coiled-coil (TACC) domains. This discovery prompted several groups to examine the role of TACC proteins during cell division, leading to indications that they are important players in this complex process in different organisms. Here, we review the current understanding of the role of TACC proteins in the regulation of microtubule dynamics, and we highlight the complexity of centrosome function.

Introduction

Cell proliferation and differentiation require dramatic rearrangements of the cytoskeleton that rely on the highly dynamic nature of the cytoskeletal components. Microtubules are dynamic filaments with fundamental roles in eukaryotic cell organization and function. During cell division, they form the bipolar spindle, which segregates the chromosomes into the two daughter cells. Microtubules show prolonged states of polymerization and depolymerization that interconvert stochastically, exhibiting frequent transitions between growing and shrinking phases, a property called ‘dynamic instability’ [1]. In the cell, multiple factors modulate this property by acting positively or negatively on the nucleation, elongation or destabilization of microtubules 1, 2, 3. The relative activity of all these factors determines the steady-state length and stability of microtubules, in addition to their organization, and it is largely dictated by global and local phosphorylation–dephosphorylation reactions 2, 3. In addition, other types of factors that have microtubule-severing and -anchoring activities also influence the microtubule network. The main microtubule-organizing centre (MTOC) of animal cells, the centrosome, acts as a platform upon which the different factors and activities accumulate in a regulated manner. It therefore exerts a tight local and temporal control on the number, distribution and polarity of microtubules 4, 5.

Transforming acidic coiled-coil (TACC) proteins emerged initially as a group of proteins implicated in cancer. The first member of the TACC family to be discovered was identified in a search of genomic regions that are amplified in breast cancer. It was named transforming acidic coiled-coil 1 (TACC1) because of its highly acidic nature, the presence of a predicted coiled-coil domain at its C terminus (now known as the TACC domain), and its ability to promote cellular transformation [6]. TACC proteins are present in different organisms, ranging from yeasts to mammals. There is only one TACC protein in the nematode Caenorhabditis elegans (TAC-1), in Drosophila melanogaster (D-TACC), in Xenopus laevis (Maskin), and in the fission yeast Schizosaccharomyces pombe (Alp7 also known as Mia1p); by contrast, mammals have three such proteins (TACC1, TACC2 [also known as AZU-1 and ECTACC] and TACC3 [also known as AINT and ERIC1]) 7, 8, 9, 10, 11. Alternative splicing further increases the complexity of the TACC protein family in mammals and flies 12, 13, 14, 15, 16.

The three human genes encoding TACC proteins are all in genomic regions that are rearranged in certain cancers, and their expression is altered in cancers from different tissues. TACC1 and TACC2 are located in chromosomes 8p11 and 10q26, respectively, two regions that are implicated in breast cancer and other tumors [6], and TACC3 maps to 4p16, within a translocation breakpoint region associated with the disease multiple myeloma [17]. Although TACC1 was originally found to be upregulated in breast cancer [6], subsequent studies found that its expression is reduced in ovarian and breast cancer tissues 18, 19. TACC3 is also upregulated in several cancer cell lines, including lung cancer 17, 20; but, again, it was reported as being absent or reduced in ovarian and thyroid cancer tissues [21]. Initially, it was suggested that the TACC2 splice variant AZU-1 is a tumor suppressor in breast cancer. However, the lack of any tumor phenotype in Tacc2-knockout mice did not support this idea [22]. It therefore appears that these proteins can be upregulated or downregulated in different types of cancer or, surprisingly, even in the same type 14, 18, 19, 20, 21, 22, 23, 24, 25; as such, their putative involvement in cancer development and/or progression is unclear.

Almost at the same time as the identification of TACC1 in humans, Maskin was identified and extensively characterized as a factor involved in the regulation of mRNA translation during maturation of Xenopus oocytes [26]. Other TACC family members have also been implicated in various events related to gene regulation, including the regulation of translation, RNA maturation and gene expression (Figure 1, Table 1) 13, 25, 27, 28, 29, 30, 31, 75. However, to date, no major common role has emerged for TACC proteins in these processes. By contrast, a major breakthrough came with the identification of D-TACC as a Drosophila microtubule-associated and centrosomal protein required for centrosome activity and microtubule assembly during mitosis [12]. Since then, the idea that TACC proteins have a role in regulating microtubule assembly has gained solid support through various studies performed in different experimental systems. In the light of these data, we review here our current understanding of the role of TACC proteins at the centrosome, and we discuss some of the issues that still remain to be addressed.