Cyclin A/cdk activity and FAM122A-dependent inhibition of PP2A-B55 are essential to trigger mitosis.

Entry into mitosis has been classically attributed to the activation of cyclin B/cdk1 amplification loop by a partial pool of this kinase that becomes active at the end of G2. However, how this pool is activated is still unknown. Here we discovered a new role of the recently identified PP2A-B55 inhibitor FAM122A in triggering mitotic entry. Accordingly, the depletion of the orthologue of FAM122A in C. elegans, prevents entry into mitosis in germline stem cells. Moreover, our data in Xenopus egg extract strongly supports that FAM122A-dependent inhibition of PP2A-B55 could be the initial event promoting mitotic entry. The inhibition of this phosphatase allows the subsequent phosphorylation of first mitotic substrates by cyclin A/cdk resulting in cyclin B/cdk1 and Greatwall (Gwl) activation. However, interestingly, from Gwl activation, Arpp19/ENSA become phosphorylated and compete with FAM122A promoting its dissociation from PP2A-B55 and taking over its inhibition until the end of mitosis.