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Dynamic Regulation Of The Signaling Lipid Phosphatidylinositol 3,5‐Bisphosphate
Author(s) -
Weisman Lois S,
Jin Natsuko
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.394.3
Subject(s) - biology , microbiology and biotechnology , phosphatidylinositol , kinase , regulator , signal transduction , phosphorylation , cyclin dependent kinase , biochemistry , cell cycle , cell , gene
Cyclin dependent kinases (CDKs) are key regulators of the cell cycle, nutrient homeostasis, cell polarity and gene expression. Here we show an unexpected link between a CDK and the signaling lipid, phosphatidylinositol 3,5 bis phosphate (PI(3,5)P 2 ). PI(3,5)P 2 is required for the growth and development of fungi, plants and animals. Minor defects in the levels of this lipid underlie some neurological diseases. Moreover, PI(3,5)P 2 plays essential roles in several organs. PI(3,5)P 2 is generated by a protein complex that includes the PI3P‐5‐kinase Fab1 (called PIKfyve in mammals), the PI(3,5)P 2 lipid phosphatase, Fig4, and the scaffold protein Vac14. PI(3,5)P 2 levels are dynamic, and in response to selected signals transiently rise in both yeast and in cultured neurons. However, the upstream signaling pathways that regulate PI(3,5)P 2 were unknown. We performed screens in yeast to determine upstream regulators of PI(3,5)P 2 . Here, we show that the yeast cyclin‐dependent kinase, Pho85 and the cyclin, Pho80 are required for the transient elevation of PI(3,5)P 2 . Pho85‐Pho80 directly phosphorylates Fab1 and positively regulates the synthesis of PI(3,5)P 2 . Furthermore, we find that Pho85‐Pho80 phosphorylation of Fab1 likely generates a conformation change that regulates Fab1. We found that in neurons, PIKfyve is a negative regulator of synaptic function. Notably, the mammalian homologue of Pho85‐Pho80, Cdk5‐ p35, is similarly a negative regulator of synaptic function. This raises the possibility that Cdk5 and PIKfyve could function in the same pathway. Indeed, we find that mammalian Cdk5‐p35 directly phosphorylates peptides of mammalian Fab1/PIKfyve, and is required for the synthesis of PI(3,5)P 2 in mouse fibroblasts. These studies reveal a conserved, upstream regulator of Fab1/PIKfyve, and provide insights into how PI(3,5)P 2 is regulated. Support or Funding Information Supported by R01 GM50403 and R01 NS064015 to LSW.