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Molecular and Cellular Biology, February 2008, p. 1029-1040, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01247-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Annexin A2 Phosphorylation Mediates Cell Scattering and Branching Morphogenesis via Cofilin Activation{triangledown} ,{dagger}

Marjo de Graauw,1 Ine Tijdens,1 Mirjam B. Smeets,3 Paul J. Hensbergen,2 André M. Deelder,2 and Bob van de Water1*

Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands,1 Biomolecular Mass Spectrometry Unit, Department of Parasitology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands,2 Experimental Cardiology Laboratory, Department of Cardiology, UMC, Utrecht, The Netherlands3

Received 12 July 2007/ Returned for modification 6 August 2007/ Accepted 12 November 2007

Dynamic remodeling of the actin cytoskeleton is required for cell spreading, motility, and migration and can be regulated by tyrosine kinase activity. Phosphotyrosine proteomic screening revealed phosphorylation of the lipid-, calcium-, and actin-binding protein annexin A2 (AnxA2) at Tyr23 as a major event preceding ts-v-Src kinase-induced cell scattering. Expression of the phospho-mimicking mutant Y23E-AnxA2 itself was sufficient to induce actin reorganization and cell scattering in MDCK cells. While Y23E-AnxA2, but not Y23A-AnxA2, enhanced Src- or hepatocyte growth factor (HGF)-induced cell scattering, short hairpin RNA-mediated knockdown of AnxA2 inhibited both v-Src- and HGF-induced cell scattering. Three-dimensional branching morphogenesis was induced in wild-type-AnxA2-expressing cells only in the presence of HGF, while Y23E-AnxA2 induced HGF-independent branching morphogenesis. Knockdown of AnxA2 prevented lumen formation during cystogenesis. The Y23E-AnxA2-induced scattering was associated with dephosphorylation/activation of the actin-severing protein cofilin. Likewise, inactive S3E-cofilin and constitutively active LIM kinase, a direct upstream kinase of cofilin, inhibited Y23E-AnxA2-induced scattering. Together, our studies indicate an essential role for AnxA2 phosphorylation in regulating cofilin-dependent actin cytoskeletal dynamics in the context of cell scattering and branching morphogenesis.

* Corresponding author. Mailing address: Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratoria, P.O. Box 9502, 2300 RA Leiden, The Netherlands. Phone: 31-71-5276223. Fax: 31-71-5274277. E-mail: b.water{at}lacdr.leidenuniv.nl

{triangledown} Published ahead of print on 10 December 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, February 2008, p. 1029-1040, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01247-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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