Role of centrosomal adaptor proteins of the TACC family in the regulation of microtubule dynamics during mitotic cell division

Abstract

During the mitotic division cycle, cells pass through an extensive microtubule rearrangement process where microtubules forming the mitotic spindle apparatus are dynamically instable. Several centrosomal- and microtubule-associated proteins are involved in the regulation of microtubule dynamics and stability during mitosis. Here, we focus on members of the transforming acidic coiled coil (TACC) family of centrosomal adaptor proteins, in particular TACC3, in which their subcellular localization at the mitotic spindle apparatus is controlled by Aurora-A kinase-mediated phosphorylation. At the effector level, several TACC-binding partners have been identified and characterized in greater detail, in particular, the microtubule polymerase XMAP215/ch-TOG/CKAP5 and clathrin heavy chain (CHC). We summarize the recent progress in the molecular understanding of these TACC3 protein complexes, which are crucial for proper mitotic spindle assembly and dynamics to prevent faulty cell division and aneuploidy. In this regard, the (patho)biological role of TACC3 in development and cancer will be discussed.

The Centrosomal Adaptor TACC3 and the Microtubule Polymerase chTOG Interact via Defined C-terminal Subdomains in an Aurora-A Kinase-independent Manner

“…11, B and C, and supplemental Table S1). These findings are consistent with data from electron microscopic analysis where TACC3 depicts an elongated, fiber-like appearance (34). Another abnormality of murine TACC3 represents its migration in SDS-PAGE gels at 120 -130 kDa (Fig.…”

“…11, B and C, and supplemental Table S1; Ref. 34) we conclude that TACC3 displays an dimeric to oligomeric state. Thr., thrombin.…”

Increased microtubule assembly rates influence chromosomal instability in colorectal cancer cells

“…Moreover, increased microtubule assembly rates in CIN cells can also be suppressed by partially depleting TACC3 (our unpublished results) indicating that Aurora-A might hyper-activate the TACC3-ch-TOG/CKAP5 axis. In this regard, it is of note that not only an overexpression of AURKA 18 , but also of TACC3 and CH-TOG have been linked to the etiology of various human cancers 49,50 supporting a possible link between a general hyper-activity of this microtubule plus end assembly pathway and CIN in cancer cells.…”

Subcellular localization and mitotic interactome analyses identify SIRT4 as a centrosomally localized and microtubule associated protein

“…During the G2/M-phase of the cell cycle, cells undergo a massive microtubule rearrangement that functions as an important regulatory switch and consists of microtubule nucleation, elongation, polymerization, and depolymerization 5 . The length of microtubules and their "dynamic instability" depend on an equilibrium shift between "catastrophe" (microtubule shrinkage) and "rescue" (microtubule growth) that is primarily regulated by several MAPs 3 . The dynamic status of microtubules and their (in)stability are critically regulated by post-translational modifications, including (de)acetylation of -tubulin (in particular lysine 40 [K40]) 6,7 .…”