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| Subject Categories: Membranes & Transport | Signal Transduction |
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| The EMBO Journal
(2003) 22, 6234–6244, doi:10.1093/emboj/cdg596 |
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| The phosphorylation state of an autoregulatory domain controls PACS-1-directed protein traffic |
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| Gregory K. Scott1, 5, Feng Gu2, 5, Colin M. Crump3, Laurel Thomas1, Lei Wan1, Yang Xiang4 and Gary Thomas1 |
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1 Vollum Institute, L-474, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA 2 McGill Cancer Center, McGill University, 3655, Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6, Canada 3 Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK 4 Department of Molecular and Cellular Physiology, Stanford Medical Center, Palo Alto, CA 94305, USA 5 G.K.Scott and F.Gu contributed equally to this work To whom correspondence should be addressed Gary Thomas, thomasg@ohsu.edu Received 5 June 2003; Revised 9 September 2003; Accepted 8 October 2003. |
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| Abstract |
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PACS-1 is a cytosolic sorting protein that directs the localization of membrane proteins in the trans-Golgi network (TGN)/endosomal system. PACS-1 connects the clathrin adaptor AP-1 to acidic cluster sorting motifs contained in the cytoplasmic domain of cargo proteins such as furin, the cation-independent mannose-6-phosphate receptor and in viral proteins such as human immunodeficiency virus type 1 Nef. Here we show that an acidic cluster on PACS-1, which is highly similar to acidic cluster sorting motifs on cargo molecules, acts as an autoregulatory domain that controls PACS-1-directed sorting. Biochemical studies show that Ser278 adjacent to the acidic cluster is phosphorylated by CK2 and dephosphorylated by PP2A. Phosphorylation of Ser278 by CK2 or a Ser278 Asp mutation increased the interaction between PACS-1 and cargo, whereas a Ser278Ala substitution decreased this interaction. Moreover, the Ser278Ala mutation yields a dominant-negative PACS-1 molecule that selectively blocks retrieval of PACS-1-regulated cargo molecules to the TGN. These results suggest that coordinated signaling events regulate transport within the TGN/endosomal system through the phosphorylation state of both cargo and the sorting machinery. |
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| Keywords: autoregulatory domain, CK2, Nef, PACS-1, phosphorylation |
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