QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 19, Issue 10, 4273-4286, October 2008

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E08-04-0405v1 19/10/4273    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Botelho, R. J. Articles by Emr, S. D. Search for Related Content PubMed PubMed Citation Articles by Botelho, R. J. Articles by Emr, S. D.

Assembly of a Fab1 Phosphoinositide Kinase Signaling Complex Requires the Fig4 Phosphoinositide Phosphatase

Roberto J. Botelho^*, Jem A. Efe^,, David Teis^*, and Scott D. Emr^*

*Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, 14853; and Division of Biology, University of California, San Diego, La Jolla, CA 92093-0668

Submitted April 21, 2008; Revised July 11, 2008; Accepted July 15, 2008
Monitoring Editor: John York

Phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P₂] regulates several vacuolar functions, including acidification, morphology, and membrane traffic. The lipid kinase Fab1 converts phosphatidylinositol-3-phosphate [PtdIns(3)P] to PtdIns(3,5)P₂. PtdIns(3,5)P₂ levels are controlled by the adaptor-like protein Vac14 and the Fig4 PtdIns(3,5)P₂-specific 5-phosphatase. Interestingly, Vac14 and Fig4 serve a dual function: they are both implicated in the synthesis and turnover of PtdIns(3,5)P₂ by an unknown mechanism. We now show that Fab1, through its chaperonin-like domain, binds to Vac14 and Fig4 and forms a vacuole-associated signaling complex. The Fab1 complex is tethered to the vacuole via an interaction between the FYVE domain in Fab1 and PtdIns(3)P on the vacuole. Moreover, Vac14 and Fig4 bind to each other directly and are mutually dependent for interaction with the Fab1 kinase. Our observations identify a protein complex that incorporates the antagonizing Fab1 lipid kinase and Fig4 lipid phosphatase into a common functional unit. We propose a model explaining the dual roles of Vac14 and Fig4 in the synthesis and turnover of PtdIns(3,5)P₂.

Present address: The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037.

Address correspondence to: Scott D. Emr (sde26{at}cornell.edu)

Abbreviations used: CCR, conserved cysteine-rich domain; coIP, coimmunoprecipitation; PtdIns(3,5)P₂, phosphatidylinositol-3,5-bisphosphate; HPLC, high-performance liquid chromatography; IP, immunoprecipitation; PtdInsP, phosphoinositide; V/C, vacuole-to-cytosol fluorescence ratio.

This article has been cited by other articles:

				O. C. Ikonomov, D. Sbrissa, H. Fenner, and A. Shisheva PIKfyve-ArPIKfyve-Sac3 Core Complex: CONTACT SITES AND THEIR CONSEQUENCE FOR Sac3 PHOSPHATASE ACTIVITY AND ENDOCYTIC MEMBRANE HOMEOSTASIS J. Biol. Chem., December 18, 2009; 284(51): 35794 - 35806. [Abstract] [Full Text] [PDF]

				P. Whitley, S. Hinz, and J. Doughty Arabidopsis FAB1/PIKfyve Proteins Are Essential for Development of Viable Pollen Plant Physiology, December 1, 2009; 151(4): 1812 - 1822. [Abstract] [Full Text] [PDF]

				F. Tsuruta, E. M. Green, M. Rousset, and R. E. Dolmetsch PIKfyve regulates CaV1.2 degradation and prevents excitotoxic cell death J. Cell Biol., October 19, 2009; 187(2): 279 - 294. [Abstract] [Full Text] [PDF]

				O. C. Ikonomov, D. Sbrissa, T. Ijuin, T. Takenawa, and A. Shisheva Sac3 Is an Insulin-regulated Phosphatidylinositol 3,5-Bisphosphate Phosphatase: GAIN IN INSULIN RESPONSIVENESS THROUGH Sac3 DOWN-REGULATION IN ADIPOCYTES J. Biol. Chem., September 4, 2009; 284(36): 23961 - 23971. [Abstract] [Full Text] [PDF]

				P. W. Majerus and J. D. York Phosphoinositide phosphatases and disease J. Lipid Res., April 1, 2009; 50(Supplement): S249 - S254. [Abstract] [Full Text] [PDF]