title: Interaction between LIS1 and PDE4, and its role in cytoplasmic dynein function.
abstract: LIS1, a WD40 repeat scaffold protein, interacts with components of the cytoplasmic dynein motor complex to regulate dynein-dependent cell motility. Here, we reveal that cAMP-specific phosphodiesterases (PDE4s) directly bind PAFAH1B1 (also known as LIS1). Dissociation of LIS1-dynein complexes is coupled with loss of dynein function, as determined in assays of both microtubule transport and directed cell migration in wounded monolayers. Such loss in dynein functioning can be achieved by upregulation of PDE4, which sequesters LIS1 away from dynein, thereby uncovering PDE4 as a regulator of dynein functioning. This process is facilitated by increased intracellular cAMP levels, which selectively augment the interaction of long PDE4 isoforms with LIS1 when they become phosphorylated within their regulatory UCR1 domain by protein kinase A (PKA). We propose that PDE4 and dynein have overlapping interaction sites for LIS1, which allows PDE4 to compete with dynein for LIS1 association in a process enhanced by the PKA phosphorylation of PDE4 long isoforms. This provides a further example to the growing notion that PDE4 itself may provide a signalling role independent of its catalytic activity, exemplified here by its modulation of dynein motor function.
authors.affiliation: Molecular Pharmacology Group, Davidson/Wolfson Link Bldgs, Institute of Neuroscience and Psychology, University of Glasgow, University Avenue, Glasgow G128QQ, UK. hannah.murdoch@glasgow.ac.uk
authors.forename: Hannah
authors.initials: H
authors.lastname: Murdoch
authors.forename: Suryakiran
authors.initials: S
authors.lastname: Vadrevu
authors.forename: Anke
authors.initials: A
authors.lastname: Prinz
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Dunlop
authors.forename: Enno
authors.initials: E
authors.lastname: Klussmann
authors.forename: Graeme B
authors.initials: GB
authors.lastname: Bolger
authors.forename: James C
authors.initials: JC
authors.lastname: Norman
authors.forename: Miles D
authors.initials: MD
authors.lastname: Houslay
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004398:Dyneins / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D010766:Phosphorylation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: D008869:Microtubule-Associated Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004398:Dyneins