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.
"Prior to this finding , the cytoskeletal functions of TACC3 were well - characterized primarily at the centrosome and mitotic spindle , where TACC3 is necessary for XMAP215 recruitment and astral and spindle MT elongation ( Lee et al . , 2001 ; Peset and Vernos , 2008 ; Lioutas and Vernos , 2013 ; Thakur et al . , 2014 ) . "
[Show abstract][Hide abstract] ABSTRACT: The growth cone is a dynamic cytoskeletal vehicle, which drives the end of a developing axon. It serves to interpret and navigate through the complex landscape and guidance cues of the early nervous system. The growth cone's distinctive cytoskeletal organization offers a fascinating platform to study how extracellular cues can be translated into mechanical outgrowth and turning behaviors. While many studies of cell motility highlight the importance of actin networks in signaling, adhesion, and propulsion, both seminal and emerging works in the field have highlighted a unique and necessary role for microtubules (MTs) in growth cone navigation. Here, we focus on the role of singular pioneer MTs, which extend into the growth cone periphery and are regulated by a diverse family of microtubule plus-end tracking proteins (+TIPs). These +TIPs accumulate at the dynamic ends of MTs, where they are well-positioned to encounter and respond to key signaling events downstream of guidance receptors, catalyzing immediate changes in microtubule stability and actin cross-talk, that facilitate both axonal outgrowth and turning events.
"We noted that the C-terminal domain was particularly well-conserved, with 80% identity among the three species. This domain, called the TACC domain (which contains two coiled-coil domains), is known to be well-conserved throughout the TACC family [Gergely et al., 2000; Peset and Vernos, 2008]. We also observed that while Xenopus laevis TACC1 and TACC3 are only 35% identical , the TACC domains are 53% identical and 71% similar between these family members (Fig. S1B in Supporting Information). "
"However, despite the well-known localization of XMAP215 at growing MT plus ends (Brouhard et al., 2008), it has been unclear whether vertebrate TACC3 interacts with XMAP215 specifically at plus ends during interphase. There has been some evidence that, in other systems, TACC proteins may bind to and regulate the plus ends of MTs (Peset and Vernos, 2008). Whereas the single TACC orthologue in Drosophila (called D-TACC) is highly concentrated at centrosomes in vivo (Gergely et al., 2000b), green fluorescent protein (GFP)–tagged D- TACC was also observable as small puncta that emanate from the centrosome, likely corresponding to growing MT plus ends (Lee et al., 2001). "
[Show abstract][Hide abstract] ABSTRACT: Microtubule plus-end dynamics are regulated by a conserved family of proteins called 'plus-end-tracking proteins' (+TIPs). Yet, it is still unclear how various +TIPs interact with each other and with plus-ends to control microtubule behavior. The centrosome-associated protein TACC3, a member of the transforming acidic coiled coil (TACC) domain family, has been previously implicated in regulating several aspects of microtubule dynamics. However, TACC3 has not been shown to function as a +TIP in vertebrates. Here, we show that TACC3 promotes axon outgrowth and regulates microtubule dynamics by increasing microtubule plus-end velocities in vivo. We also demonstrate that TACC3 acts as a +TIP in multiple embryonic cell types, and that this requires the conserved C-terminal TACC domain. Using high-resolution live-imaging data of tagged +TIPs, we reveal that TACC3 localizes to the extreme microtubule plus-end, where it lies distal to the microtubule polymerization marker, EB1, and directly overlaps with the microtubule polymerase, XMAP215. TACC3 also plays a role in regulating XMAP215 stability and localizing XMAP215 to microtubule plus-ends. Together, our results implicate TACC3 as a +TIP that functions with XMAP215 to regulate microtubule plus-end dynamics.
Molecular Biology of the Cell 09/2014; 25(21). DOI:10.1091/mbc.E14-06-1121 · 4.47 Impact Factor
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