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Interaction between LIS1 and PDE4, and its role in cytoplasmic dynein function

Item Type:Article
Title:Interaction between LIS1 and PDE4, and its role in cytoplasmic dynein function
Creators Name:Murdoch, H. and Vadrevu, S. and Prinz, A. and Dunlop, A.J. and Klussmann, E. and Bolger, G.B. and Norman, J.C. and Houslay, M.D.
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.
Keywords:cAMP, Phosphodiesterase-4, PDE4, LIS1, Rolipram, PAFAH1B1, Animals, Cercopithecus aethiops
Source:Journal of Cell Science
ISSN:0021-9533
Publisher:Company of Biologists (U.K.)
Volume:124
Number:Pt 13
Page Range:2253-2266
Date:1 July 2011
Official Publication:https://doi.org/10.1242/jcs.082982
PubMed:View item in PubMed

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