HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE ADVANCED SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Adachi, A. Articles by Murata, M. Search for Related Content PubMed Articles by Adachi, A. Articles by Murata, M.

¹ Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Komaba 3-8-1, Meguro-ku, Tokyo 153-8902, Japan
² PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan
³ Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama 351-0198, Japan

Membrane trafficking is an important cellular process that enables the precise localization of membrane proteins. The disturbance of membrane trafficking results in various disease states. To explore systematically the defects in trafficking pathways that cause these disturbances or disease states, we developed an automated high-throughput fluorescence-based imaging system and carried out visual screening for kinase-regulated trafficking pathways of the cation-independent mannose 6-phosphate receptor (CI-M6PR) in HeLa cells. As the result of our visual screening, which examined the effect of kinase inhibitors and a kinase siRNA library, we identified five kinases (CDC42BPB, PRKACA, PRKACG, GSK3β and CSNK2A1) that regulate CI-M6PR trafficking. Moreover, we focused on Alzheimer's disease (AD) to study the relationship between the five kinases and a disease state. Notably, two trafficking pathways, which were regulated by PRKACG and GSK3β, respectively, induced high levels of secretion of Aβ, the hallmark of AD. In addition, we found that the modulation of GSK3β activity affected the microtubule plus end tracking function of cytoplasmic linker protein-associating protein 2 and resulted in the perturbation of BACE1 localization/trafficking and extensive Aβ secretion. Our systems provide new approaches for the analysis of spatially-regulated membrane trafficking and related disease states.

^* Correspondence: mmurata{at}bio.c.u-tokyo.ac.jp