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THE COUNCIL FOR TOBACCO RESraxcx-U.S. A.. INC. JOO TIIIRD .1VENUE NEWYORK. N. Y. 10022 MHROrandLIItl To: Dr. H.McAllister and Staff Fran: D.H.Ford Re: Site visit with Dr.Richard Andersrn, University of Wiscarnsin , Madisaz,WI July 20, 1993 Grant No. 3130R2 entitled "Regulation of PIP Kinases and Protein 4.1 by Grcwth Factcr Receptcx Tyrcsine Phcsphcgylaticn." Aims: To determine the significance of the associaticn of type I and II phosphatidylinositol 4-phosphate-5 kinases with a protein 4.1 homolog. Are protein 4.1 isoforms tyrosine phosph~lated and/or spatially reorganized upon EGF activation? Does EdF stimulate expression of novel isoforms of protein 4.1. Does EGF stimulate membrane assembly or spatial reorganization of the PIP kinases and do protein 4.1 isoforms regulate or spatially localize PIP kinases in EGF-stimulated cells? Finally, which PIP kinases and protein 4.1 isoforms are localized in or on the cell nucleus and are they altered by EGF stimulation. Results: The progress made by Dr. Anderson on this project is well summarized in his mini and larger progress reports submitted with his R2 application. Briefly: PIP I appears to play an important role in Ca++ secretion and in the role of ATP in secretion. Anderson has now shown that both PIP I and II stimualte ATP priming and that type II PIP kinase stimulation acted synergistically with PI transferase. The precise role of PIP II is not yet clear, but it:appears that it may play a role in cell growth. Dr. Anderson has developed antibodies to both type I and II PIP kinases and observed an intracellular membrane associated localization. This is contrary to what was previously assumed, which was h~'ese r`'4r kinases were localized essentially on the cell membrane. Anderson feels that this may only represent a final localization which is associated with a role in secretion. He further concludes from his studies . . at this time that the PIP kinases may in some way be involved with the function of the intracellular motors in- volved in cell division as well as in vesicular transport. In a recent collaborative study with Dr. Martin (also at Univ. of Wisconsin), Dr. Anderson has shown that PI transferase, which stimulates the ATP-priming step in secretion (is just one of the required components) is regulated by PIP and PIP2. Since this whole sequence of proteins, etc., has been observed to be present in axons and axon terminals of catecholaminergic neurons with the kinases showing a localization on synaptic vessicles as well, it appears likely that PIP I,plays a role in release of CA. Another role for the PI transferase, which Anderson is evaluating is that it is important in the transfer of PIP kinases from one membrane system to another. Comment: An interesting and intriguing study with wide applications in cellular biology in both health and diseas. DHF