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First published online May 24, 2006
doi: 10.1242/10.1242/jcs.02941
Research Article |
1 Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden
2 Department of Pharmacological Science and the Center for Developmental Genetics, Stony Brook University, Stony Brook, New York 11794, USA
Author for correspondence (e-mail: Sven-Olof.Olofsson{at}wlab.gu.se)
Accepted 15 February 2006
We have previously uncovered roles for phospholipase D (PLD) and an unknown cytosolic protein in the formation of cytosolic lipid droplets using a cell-free system. In this report, PLD1 has been identified as the relevant isoform, and extracellular signal-regulated kinase 2 (ERK2) as the cytosolic protein. Increased expression of PLD1 increased lipid droplet formation whereas knockdown of PLD1 using siRNA was inhibitory. A role for ERK2 in basal lipid droplet formation was revealed by overexpression or microinjection, and ablation by siRNA knockdown or pharmacological inhibition. Similar manipulations of other Map kinases such as ERK1, JNK1 or JNK2 and p38
or p38ß were without effect. Insulin stimulated the formation of lipid droplets and this stimulation was inhibited by knockdown of PLD1 (by siRNA) and by inhibition or knockdown (by siRNA) of ERK2. Inhibition of ERK2 eliminated the effect of PLD1 on lipid droplet formation without affecting PLD1 activity, suggesting that PLD1 functions upstream of ERK2. ERK2 increased the phosphorylation of dynein which increased the amount of the protein on ADRP-containing lipid droplets. Microinjection of antibodies to dynein strongly inhibited the formation of lipid droplets, demonstrating that dynein has a central role in this formation. Thus dynein is a possible target for ERK2.
Key words: Phospholipase D1, Extracellular signal-regulated kinase 2 (ERK2), Cytosolic lipid droplets, Insulin, Dynein, Phosphorylation, Adipocyte differentiation-related protein (ADRP)
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