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Suppression of Synaptotagmin II restrains phorbolester-induced downregulation of protein kinase C by diverting the kinase from a degradative pathway to the recycling endocytic compartment

Department of Cell Biology and Histology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

^* Author for correspondence (e-mail: histol3{at}post.tau.ac.il )

Accepted 1 May 2002

Downregulation of protein kinase C (PKC) following long-term exposure to phorbol esters such as TPA is traffic dependent and involves delivery of the active, membrane-associated PKC to endosomes. In this study, we show that synaptotagmin II (Syt II), a member of the Syt family of proteins, is required for TPA-induced degradation of PKC. Thus, whereas the kinase half-life in TPA-treated cultured mast cells (the mast cell line rat basophilic leukemia RBL-2H3) is 2 hours, it is doubled in RBL-Syt II^- cells, in which the cellular level of Syt II is reduced by >95% by transfection with Syt II antisense cDNA. We demonstrate that in TPA-treated RBL cells, PKC travels from the cytosol to the plasma membrane, where it is delivered to early endosomes on its route to degradation. By contrast, in TPA-treated RBL-Syt II^- cells, PKC is diverted to recycling endosomes and remains distributed between the plasma membrane and the perinuclear recycling endocytic compartment. Notably, in both RBL and RBL-Syt II^- cells, a fraction of PKC is delivered and maintained in the secretory granules (SG). These results implicate Syt II as a critical factor for the delivery of internalized cargo for degradation. As shown here, one consequence of Syt II suppression is a delay in PKC downregulation, resulting in its prolonged signaling.

Key words: Protein kinase C, Synaptotagmin, TPA, Mast cells, Endosome

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