ARPP19 Phosphorylations by PKA and Greatwall: The Yin and the Yang of the Cell Decision to Divide

Abstract

Entry into mitosis and meiosis is orchestrated by the phosphorylation of thousands of mitotic substrates under the control of active Cdk1-cyclin B complexes. To avoid futile cycles of phosphorylation/dephosphorylation, the specific Cdk1-antagonizing phosphatase, PP2A-B55δ, must be simultaneously inactivated. This process is achieved by the activation of the kinase Greatwall (Gwl), which phosphorylates ARPP19. Gwlphosphorylated ARPP19 then inactivates PP2A-B55δ to allow Cdk1 activation as well as to secure the phosphorylation state of mitotic substrates. This chapter discusses a series of recent works showing that ARPP19 is also phosphorylated by another kinase, PKA. Phosphorylated by PKA, ARPP19 arrests Xenopus oocytes in G2 before the first meiotic division. Therefore, depending on its phosphorylation state by either PKA or Gwl, ARPP19 either restrains or activates Cdk1 in Xenopus oocytes. Beyond the understanding of the mechanisms of meiotic and mitotic cell division, the control of ARPP19 by its dual phosphorylation enlightens the cAMP-regulated signalization pathways that control vital functions in numerous eukaryotic cell types.

Translational Control of Xenopus Oocyte Meiosis: Toward the Genomic Era

“…This event is critical for meiosis resumption as the overexpression of a phosphomimic mutant form of Arpp19 (S109D) impairs Cdk1 activation induced by either progesterone or PKI [49]. This initial function of Arpp19 as a PKA substrate is fully distinct from the second one operating at the time of MPF activation when Arpp19 becomes phosphorylated at a distinct site (S67) by the kinase Greatwall [52][53][54]. The mechanism by which PKA-phosphorylated Arpp19 inhibits Cdk1 activation has not been yet elucidated.…”

The M-phase regulatory phosphatase PP2A-B55δ opposes protein kinase A on Arpp19 to initiate meiotic division

“…Cdk1 activation depends on PP2A-B55δ inhibition thanks to Arpp19 phosphorylation at S67 that occurs at GVBD 19 . This negative action of PP2A-B55δ is controlled by Cdk1 itself, which indirectly activates Gwl, constituting a positive feedback loop 4 . Remarkably, our present results reveal that PP2A-B55δ also positively regulates meiosis resumption by dephosphorylating Arpp19 at S109 upstream Cdk1 activation, as early as 1h after progesterone stimulation 3 .…”

“…As a result, Arpp19 is dephosphorylated at S109 and unlocks a signaling pathway that leads within 3 to 5h to the activation of the Cdk1-Cyclin B complex, or MPF (M-phase promoting factor), the universal inducer of eukaryotic cell division. Once activated, Cdk1-Cyclin B complexes trigger the resumption of the first meiotic cell division which starts with nuclear envelope breakdown, termed germinal vesicle breakdown (GVBD) in oocytes 4 .…”

“…Upon hormonal stimulation, its dephosphorylation at S109 occurs within 1h and unlocks a signaling pathway leading to meiotic division. At the very end of this molecular pathway, 3 to 5h later, Arpp19 is phosphorylated at S67 by Gwl and inactivates PP2A-B55δ, hence promoting Cdk1-Cyclin B activation 4 .…”

“…In Xenopus oocyte, it is clearly established that S67 phosphorylation of Arpp19 by Gwl promotes its binding to PP2A-B55δ and the inhibition of the phosphatase 18,19 . Released from the activity of its opposite enzyme, Cdk1 phosphorylates its two antagonistic regulators, Cdc25 and Myt1, setting up the positive feedback loop responsible for its abrupt and full activation 4 . Importantly, the Gwl/Arpp19/PP2A-B55δ module is under the control of Cdk1, being included inside the autoactivation loop.…”