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J. Biol. Chem., Vol. 278, Issue 6, 4205-4215, February 7, 2003

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Secretion of Annexin II via Activation of Insulin Receptor and Insulin-like Growth Factor Receptor^*

Wei-Qin Zhao^§¶, Gina H. Chen, Hui Chen, Alessia Pascale^**, Lakshmi Ravindranath^§, Michael J. Quon, and Daniel L. Alkon^§

From the  Laboratory of Adaptive Systems, NINDS, National Institutes of Health, Bethesda, Maryland 20892, ^§ Blanchette Rockefeller Neurosciences Institutes, Rockville, Maryland 20850,  Diabetes Unit, LCI, NCCAM, National Institutes of Health, Bethesda, Maryland 20892, and the ^** Department of Experimental and Applied Pharmacology, University of Pavia, Pavia, Italy

Annexin II is secreted into the extracellular environment, where, via interactions with specific proteases and extracellular matrix proteins, it participates in plasminogen activation, cell adhesion, and tumor metastasis and invasion. However, mechanisms regulating annexin II transport across the cellular membrane are unknown. In this study, we used coimmunoprecipitation to show that Annexin-II was bound to insulin and insulin-like growth factor-1 (IGF-1) receptors in PC12 cells and NIH-3T3 cells overexpressing insulin (NIH-3T3^IR) or IGF-1 receptor (NIH-3T3^IGF-1R). Stimulation of insulin and IGF-1 receptors by insulin caused a temporary dissociation of annexin II from these receptors, which was accompanied by an increased amount of extracellular annexin II detected in the media of PC12, NIH-3T3^IR, and NIH-3T3^IGF-1R cells but not in that of untransfected NIH-3T3 cells. Activation of a different growth factor receptor, the platelet-derived growth factor receptor, did not produce such results. Tyrphostin AG1024, a tyrosine kinase inhibitor of insulin and IGF-1 receptor, was shown to inhibit annexin II secretion along with reduced receptor phosphorylation. Inhibitors of a few downstream signaling enzymes including phosphatidylinositol 3-kinase, pp60c-Src, and protein kinase C had no effect on insulin-induced annexin II secretion, suggesting a possible direct link between receptor activation and annexin II secretion. Immunocytochemistry revealed that insulin also induced transport of the membrane-bound form of annexin II to the outside layer of the cell membrane and appeared to promote cell aggregation. These results suggest that the insulin receptor and its signaling pathways may participate in molecular mechanisms mediating annexin II secretion.

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