Research Interests
My laboratory is interested in the regulatory interfaces between novel lipid-mediated signal transduction pathways and important cellular functions. The focus of our work is the phosphatidylinositol/phosphatidylcholine transfer proteins (PITPs), a ubiquitous but enigmatic class of proteins, whose in vivo function interfaces with Golgi secretory function and cellular differentiation in yeast, signaling in the Drosophila visual and olfactory systems, growth factor signaling in mammalian cells, and pathways for the maintenance of neuronal viability in mammals. Our collective evidence indicates that PITPs coordinate key interfaces of lipid-driven metabolic reactions and intracellular signaling pathways in both yeast and mammals. Inappropriate regulation of these interfaces compromises membrane trafficking events, growth factor receptor function, cell growth control, and regulation of key developmental pathways. Because defects in any one of these pathways define recognized mechanisms of disease, PITPs represent essentially unstudied regulators whose dysfunction is likely to influence the activities of cellular processes required for cellular homeostasis.

In the past year, we have made significant advances in our mammalian and yeast projects. For the purposes of this report, we will higlight the mammalian work only. We have developed a mouse line that is defective for a specific isoform of murine PITP (i.e. PITPa). This mouse develops to term, but then expires within the first 11 days of life from neurological defects that lead to starvation in at least the most long-lived mice. The present evidence indicates that the PITPa-deficient mouse exhibits reduced motor neuron number in the spinal chord and is perhaps also defective in development of dendrites in these motor neurons. In addition, the reduced brain size of these mice suggests that the mouse generally suffers from reductions in functional neurons. In what may be a related process, the knockout mice suffer from a robust cerebellar and brain stem inflammatory disease. With this mouse model, we can now address the physiological function of mammalian PITPs for the first time. The surprising result we have obtained is that these proteins are tightly coupled to very specific signaling pathways. In the case of PITPa, this coupling may be to a specific neurotrophin receptor whose identity we are now attempting to discern. On a related note, we have discovered that the highly homologous PITPb isoform is essential for murine survival, and that PITPb defects are likely lethal at the single cell level. Thus, PITPb is an essential housekeeping PITP. We are presently developing methods to address PITPb function at the cellular level.

Publications
Wu, W.-I., Routt, S., Bankaitis, V.A., and Voelker, D. 2000. A new gene involved in transport-dependent metabolism of phosphatidylserine, PSTB2/PDR17, shares sequence similarity with the gene encoding the phosphatidylinositol/phosphatidylcholine transfer protein, Sec14p. J. Biol. Chem. 275: 14446-14456.

Li, X., Routt, S., Xie, Z., Cui, X., Fang, M., Kearns, M.A., Bard, M., Kirsch, D. and Bankaitis, V.A. 2000. Identification of a novel family of nonclassical yeast PITPs whose function modulates phospholipase D activity and Sec14p-independent cell growth. Mol. Biol. Cell 11: 1989-2005.

Nemoto, Y., Kearns, B.G., Wenk, M.R., Chen, H., Mori, K., Alb, J.G., Jr., De Camilli, P., and Bankaitis, V.A. 2000. Functional characterization of a mammalian Sac1 and mutants exhibiting substrate specific defects in phosphoinositide phosphatase activity. J. Biol. Chem. 275: 14446-14456.

Nakase, Y., Nakamura, T., Hirata, A., Routt, S.M., Skinner, H., Bankaitis, V.A. and Shimoda, C. 2001. The S. pombe spo20+ gene encoding a homologue of S. cerevisiae Sec14p plays an important role in forespore membrane formation. Mol. Biol. Cell 12: 901-917.

Xie, Z., Fang, M. and Bankaitis, V.A. 2001. Evidence for an intrinsic toxicity of phosphatidylcholine to Sec14p-dependent protein transport from the yeast Golgi complex. Mol. Biol. Cell 12: 1117-1129.

Kapranov, P., Routt, S.M., Bankaitis, V.A., de Bruijn, F.J. and Szczyglowski, K. 2001. Novel developmental regulation of phosphatidylinositol transfer protein expression in nitrogen-fixing root nodules of the flowering plant Lotus japonicus. Plant Cell 13: 1369-1382.

E-mail: bktis@med.unc.edu
Telephone: 919-966-3026
Address: 108 Taylor Hall Chapel Hill, NC

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