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A more recent version of this article appeared on March 1, 2002
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Submitted on September 18, 2001
Revised on November 29, 2001
Accepted on December 12, 2001
1 Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7090
2 Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294
3 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294
4 Department of Physiology, University College London, London, United Kingdom
5 Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294
6 Howard Hughes Medical Institute, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710
* Corresponding author. E-mail address: bktis{at}med.unc.edu.
Phosphatidylinositol transfer proteins (PITPs) regulate the interface between signal transduction, membrane-trafficking and lipid metabolic pathways in eukaryotic cells. The best characterized mammalian PITPs are PITP
and PITPß, two highly homologous proteins that are encoded by distinct genes. Insights into PITP and PITPß function in mammalian systems have been gleaned exclusively from cell-free or permeabilized cell reconstitution and resolution studies. Herein, we report for the first time the use of genetic approaches to directly address the physiological functions of PITP and PITPß in murine cells. Contrary to expectations, we find that ablation of PITP function in murine cells fails to compromise growth and has no significant consequence for bulk phospholipid metabolism. Moreover, the data show that PITP does not play an obvious role in any of the cellular activities where it has been reconstituted as an essential stimulatory factor. These activities include: protein trafficking through the constitutive secretory pathway, endocytic pathway function, biogenesis of mast cell dense core secretory granules (DSGs), and the agonist-induced fusion of DSGs to the mast cell plasma membrane. Finally, the data demonstrate that PITP-deficient cells not only retain their responsiveness to bulk growth factor stimulation, but also retain their pluripotency. By contrast, we were unable to evict both PITPß alleles from murine cells, and show that PITPß deficiency results in catastrophic failure early in murine embryonic development. We suggest that PITPß is an essential housekeeping PITP in murine cells whereas PITP plays a far more specialized function in mammals than that indicated by in vitro systems that show PITP-dependence.
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