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Vol. 17, Issue 9, 3989-4001, September 2006

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Fab1 Phosphatidylinositol 3-Phosphate 5-Kinase Controls Trafficking but Not Silencing of Endocytosed Receptors

Tor Erik Rusten^*, Lina M.W. Rodahl^*, Krupa Pattni^*, Camilla Englund, Christos Samakovlis, Stephen Dove, Andreas Brech^*, and Harald Stenmark^*

*Department of Biochemistry, The Norwegian Radium Hospital and the University of Oslo, Montebello, N-0310 Oslo, Norway; Department of Developmental Biology, Wenner-Gren Institute, Stockholm University, S-106 91 Stockholm, Sweden; and Department of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom

Submitted March 27, 2006; Revised June 13, 2006; Accepted July 3, 2006
Monitoring Editor: Jean Gruenberg

The trafficking of endocytosed receptors through phosphatidylinositol 3-phosphate [PtdIns(3)P]-containing endosomes is thought to attenuate their signaling. Here, we show that the PtdIns(3)P 5-kinase Fab1/PIKfyve controls trafficking but not silencing of endocytosed receptors. Drosophila fab1 mutants contain undetectable phosphatidylinositol 3,5-bisphosphate levels, show profound increases in cell and organ size, and die at the pupal stage. Mutant larvae contain highly enlarged multivesicular bodies and late endosomes that are inefficiently acidified. Clones of fab1 mutant cells accumulate Wingless and Notch, similarly to cells lacking Hrs, Vps25, and Tsg101, components of the endosomal sorting machinery for ubiquitinated membrane proteins. However, whereas hrs, vps25, and tsg101 mutant cell clones accumulate ubiquitinated cargo, this is not the case with fab1 mutants. Even though endocytic receptor trafficking is impaired in fab1 mutants, Notch, Wingless, and Dpp signaling is unaffected. We conclude that Fab1, despite its importance for endosomal functions, is not required for receptor silencing. This is consistent with the possibility that Fab1 functions at a late stage in endocytic receptor trafficking, at a point when signal termination has occurred.

Address correspondence to: Harald Stenmark (stenmark{at}ulrik.uio.no)

Abbreviations used: BSA, bovine serum albumin; EM, electron microscopy; ESCRT, endosomal sorting complex required for transport; GFP, green fluorescent protein; HRP, horseradish peroxidase; MVB, multivesicular body; OGD, Oregon green dextran; PI, phosphoinositide; TRD, Texas Red dextran.

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