title: 14-3-3 zeta mediates integrin-induced activation of Cdc42 and Rac. Platelet glycoprotein Ib-IX regulates integrin-induced signaling by sequestering 14-3-3 zeta.
abstract: Integrin-induced cytoskeletal reorganizations are initiated by Cdc42 and Rac1 but little is known about mechanisms by which integrins activate these Rho GTPases. 14-3-3 proteins are adaptors implicated in binding and regulating the function and subcellular location of numerous signaling molecules. In platelets, the 14-3-3 zeta isoform interacts with the glycoprotein (GP) Ibalpha subunit of the adhesion receptor GP Ib-IX. In this study, we show that integrin-induced activation of Cdc42, activation of Rac, cytoskeletal reorganizations, and cell spreading were inhibited in Chinese hamster ovary cells expressing full-length GP Ibalpha compared with GP Ibalpha lacking the 14-3-3 zeta binding site. Activation of Rho GTPases and cytoskeletal reorganizations were restored by expression of 14-3-3 zeta. Spreading in cells expressing truncated GP Ibalpha was inhibited by co-expressing a chimeric receptor containing interleukin 2 receptor alpha and GP Ibalpha cytoplasmic domain. These results identify a previously unrecognized function of 14-3-3 zeta, that of mediating integrin-induced signaling. They show that 14-3-3 zeta mediates Cdc42 and Rac activation. They also reveal a novel function of platelet GP Ib-IX, that of regulating integrin-induced cytoskeletal reorganizations by sequestering 14-3-3 zeta. Signaling across integrins initiates changes in cell behavior such as spreading, migration, differentiation, apoptosis, or cell division. Thus, introduction of the 14-3-3 zeta binding domain of GP Ibalpha into target cells might provide a method for regulating integrin-induced pathways in a variety of pathological conditions.
authors.affiliation: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, the Lerner Research Institute, the Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bialkowska
authors.forename: Yona
authors.initials: Y
authors.lastname: Zaffran
authors.forename: Sylvie C
authors.initials: SC
authors.lastname: Meyer
authors.forename: Joan E B
authors.initials: JE
authors.lastname: Fox
mesh_terms: D048948:14-3-3 Proteins; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D016466:CHO Cells; D002448:Cell Adhesion; D002454:Cell Differentiation; D002455:Cell Division; D002465:Cell Movement; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D005982:Glutathione Transferase / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism* / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D018076:DNA, Complementary; D016023:Integrins; D019038:Platelet Glycoprotein GPIb-IX Complex; D020033:Protein Isoforms; D014446:Tyrosine 3-Monooxygenase; D005982:Glutathione Transferase; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins