Research interest
Our group has a longstanding interest in lipid growth factors in particular lysophosphatidic acid (LPA), its signaling properties and role in health and disease. LPA signals through several G protein-coupled receptors to elicite a wide range of cellular responses, ranging from cell proliferation and migration to neurite remodeling and cytokine production. LPA is produced by a secreted lysophospholipase D (lysoPLD), named autotaxin (ATX), an autocrine motility factor implicated in tumor progression. Genetic studies in mice indicate that ATX is essential for vascular development. Our current research focuses on the ATX-LPA axis, in particular the regulation of its activity, its signaling properties, its impact on gene trancription and its role in tumor progression and angiogenesis. In addition, we closely collaborate with the chemistry group of Dr. Huib Ovaa to develop newly discovered small-molecule inhibitors of ATX that are being tested for their anti-cancer potential.
A second line of research is devoted to the regulation of cell-cell communication via gap junctions. Gap junctional communication is fundamental to coordinated cell behavior and is often defective in tumor cells. We recently identified phosphatidyl (4,5)-bisphosphate, a signaling lipid in the plasma membrane, as a key regulator of gap junctional communication in normal cells.
In our studies we make use of a variety of biochemical, biophysical and cell biological techniques. The in vivo functions of ATX are investigated in tissue-specifc knockout mice.
Key publications
Van Meeteren LA, Moolenaar WH. Regulation and biological activities of the ATX-LPA axis. Progr Lipid Res (2007)
Van Zeijl L, Ponsioen B, Giepmans B, Ariaens A, Postma F, Várnai P, Balla T, Divecha N, Jalink K, Moolenaar WH. Regulation of connexin43 gap junctional communication by phosphatidylinositol 4,5-bisphosphate. J Cell Biol (2007)
Van Meeteren LA, Ruurs P, Stortelers C, Bouwman P, van Rooijen M, Pradere J, Pettit T, Wakelam M, Saulnier-Blache J, Mummery C, Moolenaar WH, Jonkers J. Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development. Mol Cell Biol 26:5015-22 (2006).
Sayas C, Ariaens A, Ponsioen B, Moolenaar WH. GSK-3 is activated by the tyrosine kinase Pyk2 downstream of LPA1: role in neurite retraction. Mol Biol Cell 17:1834-44 (2006).
Van Meeteren LA, Ruurs P, Christodoulou E, Goding J, Takakusa H, Kikuchi K, Perrakis A, Nagano T, Moolenaar WH. Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate. J Biol Chem. 280:21155-61 (2005)
Moolenaar WH, van Meeteren L, Giepmans B. The ins and outs of lysophosphatidic acid signaling. Bioessays 26:870-81 (2004)
Van Meeteren LA, Frederiks F, Giepmans B, Fernandes Pedrosa M, Billington S, Jost B, Tambourgi D, Moolenaar WH. Spider and bacterial sphingomyelinases D target cellular LPA receptors by hydrolyzing lysophosphatidylcholine. J Biol Chem. 279:10833-6 (2004)
Mills GB, Moolenaar WH. The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer 3:582-91 (2003)
Van Leeuwen F, Olivo C, Grivell S, Giepmans B, Collard J, Moolenaar WH. Rac activation by LPA1 receptors through the guanine nucleotide exchange factor Tiam1. J Biol Chem. 278:400-6 (2003)
Postma F, Jalink K, Hengeveld T, Offermanns S, Moolenaar WH. G(alpha)13 mediates activation of a depolarizing chloride current that accompanies RhoA activation. Curr Biol.11:121-4 (2001)
Other publications by Wouter Moolenaar can be found on PubMed.
Biographic sketch
Wouter Moolenaar peformed his graduate research at the University of Leiden (Laboratory of Physiology) and the Weizmann Institute of Science in Israel (Department of Neurobiology) and obtained his PhD in 1978. During postdoctoral periods at the Hubrecht Labaratory (Utrecht) and the Weizmann Institute of Science, he studied growth factor signaling.
He became group leader at the Netherlands Cancer Institute in 1988 and was appointed part-time professor of molecular cell biology at Leiden University in 1996. His group was the first to discover LPA as a growth factor and to characterize many of its signaling pathways. His current research focuses on the regulation and biological activities of the autotaxin (ATX)-LPA-LPA receptor axis.
Co-workers
Maaike Alderliesten PhD Postdoc
Elisabetta Argenzio PhD Postdoc
Maikel Jongsma PhD Postdoc
Elisa Matas PhD Postdoc
Anna Houben MSc Graduate student
Dalila El Ouarrat MSc Graduate student
Michel van Veen MSc Graduate student