The PHLPP1 N-Terminal Extension is a Mitotic Cdk1 Substrate and Controls an Interactome Switch

Mol Cell Biol. 2021 Jan 4;41(3):e00333-20. doi: 10.1128/MCB.00333-20. Online ahead of print.


PH domain Leucine-Rich Repeat Protein Phosphatase 1 (PHLPP1) is a tumor suppressor that directly dephosphorylates a wide array of substrates, most notably the pro-survival kinase Akt. However, little is known about the molecular mechanisms governing PHLPP1 itself. Here we report that PHLPP1 is dynamically regulated in a cell cycle-dependent manner, and deletion of PHLPP1 results in mitotic delays and increased rates of chromosomal segregation errors. We show that PHLPP1 is hyperphosphorylated during mitosis by Cdk1 in a functionally uncharacterized region known as the PHLPP1 N-terminal extension (NTE). A proximity-dependent biotin identification (BioID) interaction screen revealed that during mitosis PHLPP1 dissociates from plasma membrane scaffolds, such as Scribble, by a mechanism that depends on its NTE, and gains proximity with kinetochore and mitotic spindle proteins such as KNL1 and TPX2. Our data are consistent with a model in which phosphorylation of PHLPP1 during mitosis regulates binding to its mitotic partners and allows accurate progression through mitosis. The finding that PHLPP1 binds mitotic proteins in a cell cycle- and phosphorylation-dependent manner may have relevance to its tumor suppressive function.