Bystanders or active players: the role of extra centrosomes as signaling hubs

Abstract

Centrosomes serve as microtubule-organizing organelles that function in spindle pole organization, cell cycle progression, and cilia formation. A non-canonical role of centrosomes that has gained traction in recent years is the ability to act as signal transduction centers. Centrosome amplification, which includes numerical and structural aberrations of centrosomes, is a candidate hallmark of cancer. The function of centrosomes as signaling centers in cancer cells with centrosome amplification is poorly understood. Establishing a model of how cancer cells utilize centrosomes as signaling platforms will help elucidate the role of extra centrosomes in cancer cell survival and tumorigenesis. Centrosomes act in a diverse array of cellular processes, including cell migration, cell cycle progression, and proteasomal degradation. Given that cancer cells with amplified centrosomes exhibit an increased number and larger area of these signaling platforms, extra centrosomes may be acting to promote tumor development by enhancing signaling kinetics in pathways that are essential for the formation and growth of cancer. In this review, we identify the processes centrosomes are involved in as signal transduction platforms and highlight ways in which cancer cells with centrosome amplification may be taking advantage of these mechanisms.

Keywords: Cancer; Cell cycle; Centrosome amplification; Centrosomes; Signaling.

Fig. 1

In G1, cell possess one centrosome with two centrioles that are physically separated. During S phase, procentrioles start to form at the base of each centriole. The procentrioles elongate during G2 and pericentriolar material (purple) starts to accumulate. At the G2/prophase interface, the linker between centrioles is cleaved so that two centrosomes are formed. The two centrosomes migrate to opposite spindle poles during mitosis and generate a bipolar spindle for proper chromosome segregation. Created with BioRender.com

Fig. 2

The PIDDosome is a multi-protein complex that acts as an internal sensor to check the integrity of centrosomes and DNA during the cell cycle. In cells without CA, PIDD1 localizes to centrosomes where it is undergoes auto-cleavage but does not cause PIDDosome formation. PIDDosome activation requires amplified centrosomes to cluster together. Clustered centrosomes locally increase the concentration of cleaved PIDD1, when then diffuses into the cytoplasm where it activates the PIDDosome and CASP2 [58]. Active CASP2 cleaves and inactivates MDM2, leading to p53 activation and p21 upregulation, ultimately arresting the cell cycle or initiating apoptosis [59]. Created with BioRender.com

Fig. 3

The consequences of LATS1 activation at the centrosome differ depending on where the cell is in the cell cycle. During mitosis, the RASSF1A-WW45-MST2 complex phosphorylates LATS, causing phosphorylation of YAP1 which translocates to the nucleus to activate p73 and promote transcription of PUMA, a proapoptotic gene [66, 69]. During interphase, LATS1 plays an important role in the regulation of centriole duplication. LATS1 interacts with the phosphatase CDC25B at the centrosome and regulates its stability, allowing for normal centriole duplication [70]. An accumulation of CDC25B causes hyperactivation of CDK2 and nucleophosmin (NPM), resulting in centriole overduplication. Created with BioRender.com

Fig. 4

A Clustering of amplified centrosomes may play an important role in the ability of centrosomes to lower activation energy barriers in specific signaling pathways or complex formation. A high number of signaling molecules associating with the centrosome may increase the number of downstream effectors activated and signaling speed. B It is possible that other proteins and pathways utilize centrosomes in this same fashion to enhance signaling kinetics. Amplified centrosomes that are clustered together may act to increase the number of signaling molecules that are activated, leading to propagation of the signal to downstream effectors and lowering the time for pathway activation. Created with BioRender.com

Fig. 5

A Localization of proteasomal machinery to centrosomes may act to increase the efficiency of protein degradation. The precise timing of the degradation of proteins involved in the cell cycle is necessary for proper cell cycle progression and proliferation. For example, the localization of LATS1, an essential regulator of centriole duplication, to the centrosome may allow the proteasome to regulate the protein level of LATS1 during interphase to properly link the centrosome cycle to the cell cycle. B When large loads of misfolded protein are present when the ubiquitin proteasome is inhibited, cells recruit proteasomal machinery from the cytosol to centrosomes. A high accumulation of misfolded protein at the centrosome is sufficient to recruit the proteasome to the centrosome where it becomes active [83, 86]. Created with BioRender.com