title: Annexin A2 phosphorylation mediates cell scattering and branching morphogenesis via cofilin Activation.
abstract: 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.
authors: Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratoria, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors: Marjo
authors: M
authors: de Graauw
authors: Ine
authors: I
authors: Tijdens
authors: Mirjam B
authors: MB
authors: Smeets
authors: Paul J
authors: PJ
authors: Hensbergen
authors: André M
authors: AM
authors: Deelder
authors: Bob
authors: B
authors: van de Water
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000378:metabolism*; D002460:Cell Line; D048430:Cell Shape; D051338:Cofilin 1 / Q000378:metabolism*; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D054461:Lim Kinases / Q000502:physiology; D010766:Phosphorylation
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; D051338:Cofilin 1; D017228:Hepatocyte Growth Factor; D054461:Lim Kinases