AKAP149 is a novel PP1 specifier required to maintain nuclear envelope integrity in G1 phase

Abstract

Reassembly of the nuclear envelope (NE) at the end of mitosis requires targeting of the B-type lamin protein phosphatase, PP1, to the envelope by A-kinase anchoring protein AKAP149. We show here that NE-associated AKAP149 is a novel PP1-specifying subunit involved in maintaining nuclear architecture through G1 phase. PP1 remains associated with NE-bound AKAP149 during G1 but is released from AKAP149 upon S phase entry, as AKAP149 becomes serine-phosphorylated. NE-associated AKAP149 inhibits PP1 activity towards glycogen phosphorylase but enhances PP1 phosphatase activity towards B-type lamins, indicating that AKAP149 is a B-type lamin specifying subunit of PP1. In vivo dissociation of PP1 from NE-bound AKAP149 in G1-phase nuclei triggers phosphorylation and depolymerization of A- and B-type lamins. The lamins solubilize intranuclearly without affecting the inner nuclear membrane or pore complex distribution. This correlates with the induction of a G1 arrest and, ultimately, apoptosis. We propose that AKAP149-regulated PP1 activity at the NE during G1 is required to maintain nuclear integrity and cell survival.