Annexin 1 regulates cell proliferation by disruption of cell morphology and inhibition of cyclin D1 expression through sustained activation of the ERK1/2 MAPK signal.
Cellular proliferation is controlled by the integration and coordination of extracellular signals. This study explores the role of the protein annexin 1 (ANXA1) in the regulation of such events. We show that ANXA1 has a cell-type independent, anti-proliferative function through sustained activation of the ERK signaling cascade. Moreover, ANXA1 reduces proliferation by ERK-mediated disruption of the actin cytoskeleton and ablation of cyclin D1 protein expression and not by ERK-mediated induction of the cyclin-dependent kinase, CDK2, inhibitor p21(cip/waf). Finally, ANXA1 regulates the ERK pathway at a proximal location, by SH2 domain-independent association with the adapter protein Grb-2. In summary, overexpression of ANXA1 mediates the disruption of normal cell morphology and inhibits cyclin D1 expression, therefore reducing cell proliferation through proximal modulation of the ERK signal transduction pathway.
D008841:Actin Cytoskeleton / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017305:Annexin A1 / Q000378:metabolism*; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D048429:Cell Size / Q000502:physiology; D019938:Cyclin D1 / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000502:physiology*; D051380:GRB2 Adaptor Protein; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000201:enzymology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008264:Macrophages / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D017305:Annexin A1; D004791:Enzyme Inhibitors; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495950:Grb2 protein, rat; D011506:Proteins; D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases