Centrosomal protein of 192 kDa (Cep192) promotes centrosome-driven spindle assembly by engaging in organelle-specific Aurora A activation

Abstract

Centrosomes are primary microtubule (MT)-organizing centers (MTOCs). During mitosis, they dramatically increase their size and MT-nucleating activity and participate in spindle assembly from spindle poles. These events require the serine/threonine kinase, Aurora A (AurA), and the centrosomal protein of 192 kDa (Cep192)/spindle defective 2 (Spd-2), but the underlying mechanism remains unclear. We have found that Cep192, unlike targeting protein for Xklp2 (TPX2), a known MT-localizing AurA activator, is an AurA cofactor in centrosome-driven spindle assembly. Cep192, through a direct interaction, targets AurA to mitotic centrosomes where the locally accumulating AurA forms homodimers or oligomers. The dimerization of endogenous AurA, in the presence of bound Cep192, triggers potent kinase activation that, in turn, drives MT assembly. Depletion of Cep192 or specific interference with AurA-Cep192 binding did not prevent AurA oligomerization on MTs but abrogated AurA recruitment to centrosomes and its activation by either sperm nuclei or anti-AurA antibody (αAurA)-induced dimerization. In these settings, MT assembly by both centrosomes and αAurA-coated beads was also abolished or severely compromised. Hence, Cep192 activates AurA by a mechanism different from that previously described for TPX2. The Cep192-mediated mechanism maximizes AurA activity at centrosomes and appears essential for the function of these organelles as MTOCs.

Aurora kinases and spindle assembly: Variations on a common theme?

“…53 Here, these findings are discussed in the context of other recent reports on the regulation of the Aurora kinases, with an emphasis on the aspects related to spindle assembly. For more detailed information on Aurora kinases, the reader is referred to several excellent reviews.…”

“…interaction, however, was dispensable for the chromatin/RanGTP-mediated MT assembly, which is the province of TPX2 53 . Thus, Cep192 and TPX2 function as distinct, targeting and activating cofactors of AurA in the centrosomal and chromatin/RanGTP-driven spindle assembly pathways, respectively.…”

Centrosomes as signalling centres

“…Instead, the timing of NEBD may depend primarily on the regulation of Aurora A activity at the centrosome. In this context, it is interesting to note that studies performed with Xenopus egg extracts identified the centrosome as a primary site for Aurora A activation [73].…”

Exploring the evolutionary history of centrosomes

“…Another possibility is that SPD-2 originally evolved to organize the poles of the mitotic spindle in Amorphea. In animals, SPD-2 family members are key to centrosome maturation, which leads to an increase in the microtubule-nucleation capacity of mitotic centrosomes required for centrosome-driven spindle assembly [121,123,124]. In chytrids and choanoflagellates, mitotic microtubules are nucleated in the immediate vicinity of the centrioles, which could involve SPD-2-dependent recruitment of microtubule-nucleating complexes.…”