AKT Regulates Mitotic Progression of Mammalian Cells by Phosphorylating MASTL, Leading to Protein Phosphatase 2A Inactivation

Abstract

Microtubule-associated serine/threonine kinase like (MASTL), also known as Greatwall (Gwl) kinase, has an important role in the regulation of mitosis. By inhibiting protein phosphatase 2A (PP2A), it plays a crucial role in activating one of the most important mitotic kinases, known as cyclin-dependent kinase 1 (CDK1). MASTL has been seen to be upregulated in various types of cancers and is also involved in tumor recurrence. It is activated by CDK1 through phosphorylations in the activation/T-loop, but the complete mechanism of its activation is still unclear. Here, we report that AKT phosphorylates MASTL at residue T299, which plays a critical role in its activation. Our results suggest that AKT increases CDK1-mediated phosphorylation and hence the activity of MASTL, which, in turn, promotes mitotic progression through PP2A inhibition. We also show that the oncogenic potential of AKT is augmented by MASTL activation, since AKT-mediated proliferation in colorectal cell lines can be attenuated by inhibiting and/or silencing MASTL. In brief, we report that AKT plays an important role in the progression of mitosis in mammalian cells and that it does so through the phosphorylation and activation of MASTL.

MASTL is enriched in cancerous and pluripotent stem cells and influences OCT1/OCT4 levels

“…Exogenous overexpression of MASTL triggers AKT activation in an ENSA/PP2A-independent manner ( Rogers et al., 2018 ; Vera et al., 2015 ). In addition, AKT-mediated proliferation in colorectal cell lines can be attenuated by MASTL silencing ( Reshi et al., 2020 ). Our results show that silencing of MASTL leads to a significant decrease in TGFBR2 levels and TGF-β-induced PI3K-AKT activation.…”

Polyomavirus Small T Antigen Induces Apoptosis in Mammalian Cells through the UNC5B Pathway in a PP2A-Dependent Manner

“…We believe that changes in the subunit composition, localization, and activity of PP2A by PyST may affect some critical cellular activities, including mitotic regulation. PP2A is known to be extremely important at the entry as well as exit of mitosis (54)(55)(56)(57). Deregulation of PP2A activity in actively dividing cells therefore leads to severe abnormalities during mitosis, as is clearly visible in PyST-expressing cells also, leading to the activation of the spindle assembly checkpoint (SAC).…”

The MASTL/PP2A cell cycle kinase‐phosphatase module restrains PI3K‐Akt activity in an mTORC1‐dependent manner

“…It is, therefore, possible that MASTL may influence AKT signaling differentially in cycling (Vera et al , 2015) or starved/G0 cells as suggested by our data. Interestingly, AKT may lead to MASTL phosphorylation and activation specifically during mitosis (Reshi et al , 2020), although whether this is mediated by direct phosphorylation and whether these data have any relevance in vivo in a physiological context have not been addressed so far.…”