A fine balancing act: A delicate kinase-phosphatase equilibrium that protects against chromosomal instability and cancer

Abstract

Cancer cells rewire signalling networks to acquire specific hallmarks needed for their proliferation, survival, and dissemination throughout the body. Although this is often associated with the constitutive activation or inactivation of protein phosphorylation networks, there are other contexts when the dysregulation must be much milder. For example, chromosomal instability is a widespread cancer hallmark that relies on subtle defects in chromosome replication and/or division, such that these processes remain functional, but nevertheless error-prone. In this article, we will discuss how perturbations to the delicate kinase-phosphatase balance could lie at the heart of this type of dysregulation. In particular, we will explain how the two principle mechanisms that safeguard the chromosome segregation process rely on an equilibrium between at least two kinases and two phosphatases to function correctly. This balance is set during mitosis by a central complex that has also been implicated in chromosomal instability - the BUB1/BUBR1/BUB3 complex - and we will put forward a hypothesis that could link these two findings. This could be relevant for cancer treatment because most tumours have evolved by pushing the boundaries of chromosomal instability to the limit. If this involves subtle changes to the kinase-phosphatase equilibrium, then it may be possible to exacerbate these defects and tip tumour cells over the edge, whilst still maintaining the viability of healthy cells.

Kinase and Phosphatase Cross-Talk at the Kinetochore

“…This may explain why modulating the Bub1/BubR1 ratio at kinetochores affects kinetochore-microtubule dynamics and tumorigenesis (Lampson and Kapoor, 2005 ; Jeganathan et al, 2007 ; Bohers et al, 2008 ; Baker et al, 2009 , 2013 ; Suijkerbuijk et al, 2010 ; Ricke and Van Deursen, 2011 ; Ricke et al, 2011 ). This is a hypothesis that is discussed in detail elsewhere (Cordeiro et al, 2018 ).…”

Benzene-induced mouse hematotoxicity is regulated by a protein phosphatase 2A complex that stimulates transcription of cytochrome P4502E1

“…Dysregulation of protein phosphorylation in signaling pathways has been linked to the development of many human diseases (32,33). Although several types of protein kinases have been shown to be directly involved in benzene-induced hematotoxicity, the key events with respect to protein phosphatase remain largely unknown.…”

Impact of physical confinement on nuclei geometry and cell division dynamics in 3D spheroids

“…This structure is associated with transient unstable interactions between kinetochores and microtubules during spindle assembly in early prometaphase 23 . Therefore, our observations strongly suggest that in conditions of physical confinement, mitotic spindle assembly and/or positioning is transiently impaired, leading to activation of the spindle assembly checkpoint 34 , 35 , and increased prometaphase duration. Spindle assembly and orientation are crucial for chromosome capture and segregation, and consequently for tissue organization and development 27 , 36 , 37 .…”