Phosphatidylinositol Phosphate Kinases, a Multifaceted Family of Signaling Enzymes

phosphatidylinositol phosphatidylinositol-phosphate kinase type I phosphatidylinositol-phosphate kinase type II phosphatidylinositol-phosphate kinase PIP, phosphatidylinositol phosphate phosphatidylinositol bisphosphate phosphatidylinositol trisphosphate cyclic adenosine monophosphate-dependent protein kinase catalytic subunit tumor necrosis factor epidermal growth factor phosphatidic acid phospholipase D The importance of phosphoinositides as lipid signaling molecules in eucaryotic cells was first recognized by Lowell and Mabel Hokin in the 1950s (who also discovered the enzyme activities that phosphorylate phosphatidylinositol (PI)1) (1Hokin M.R. Hokin L.E. J. Biol. Chem. 1953; 203: 967-977Abstract Full Text PDF PubMed Google Scholar, 2Hokin L.E. Hokin M.R. Biochim. Biophys. Acta. 1955; 18: 102-110Crossref PubMed Scopus (162) Google Scholar, 3Hokin L.E. Hokin M.R. Biochim. Biophys. Acta. 1964; 84: 563-575PubMed Google Scholar, 4Hokin M.R. Hokin L.E. Dawson R.M.C. Rhodes D.N. Metabolism and Physiological Significance of Lipids. John Wiley & Sons, Inc., New York1964: 423-434Google Scholar, 5Hokin L.E. Hokin-Neaverson M. Biochim. Biophys. Acta. 1989; 1000: 465-469Crossref PubMed Scopus (13) Google Scholar). Since those early years, PI signaling pathways have expanded both in importance and complexity. The classical pathway transforms PI to PI-4,5-P2 by the successive actions of PI 4-kinases and PI-4-P 5-kinases. PI-4,5-P2 is the precursor for second messengers and also acts directly to modify effectors, for example actin-binding proteins (6Rana R.S. Hokin L.E. Physiol. Rev. 1990; 70: 115-164Crossref PubMed Scopus (431) Google Scholar, 7Lee S.B. Rhee S.G. Curr. Opin. Cell Biol. 1995; 7: 183-189Crossref PubMed Scopus (284) Google Scholar, 8Rhee S.G. Bae Y.S. J. Biol. Chem. 1997; 272: 15045-15048Crossref PubMed Scopus (817) Google Scholar, 9Nishizuka Y. FASEB J. 1995; 9: 484-496Crossref PubMed Scopus (2368) Google Scholar). Significant roles for other phosphoinositide lipid products in signaling, combined with recently identified lipid kinase activities, are illuminating the many mechanisms by which cells use lipid messengers (10Auger K.R. Serunian L.A. Soltoff S.P. Libby P. Cantley L.C. Cell. 1989; 57: 167-175Abstract Full Text PDF PubMed Scopus (684) Google Scholar, 11Stephens L.R. Jackson T.R. Hawkins P.T. Biochim. Biophys. Acta. 1993; 1179: 27-75Crossref PubMed Scopus (426) Google Scholar, 12Toker A. Cantley L.C. Nature. 1997; 387: 673-676Crossref PubMed Scopus (1229) Google Scholar, 13Downward J. Curr. Opin. Cell Biol. 1998; 10: 262-267Crossref PubMed Scopus (1190) Google Scholar). This review will focus on the phosphatidylinositol-phosphate kinase (PIPK) family, which has the ability to synthesize all known PIP2 isomers and PIP3. Historically, in PI signaling as we understood it a few years ago, the PIPKs synthesize PI-4,5-P2 by phosphorylating the fifth hydroxyl of PI-4-P (6Rana R.S. Hokin L.E. Physiol. Rev. 1990; 70: 115-164Crossref PubMed Scopus (431) Google Scholar). Two isoforms of PIPKs were characterized from erythrocytes; these were denoted type I and II PI-4-P 5-kinase (PIPKI and PIPKII) based their biochemical properties (14Ling L.E. Schulz J.T. Cantley L.C. J. Biol. Chem. 1989; 264: 5080-5088Abstract Full Text PDF PubMed Google Scholar, 15Bazenet C.E. Ruano A.R. Brockman J.L. Anderson R.A. J. Biol. Chem. 1990; 265: 18012-18022Abstract Full Text PDF PubMed Google Scholar, 16Jenkins G.H. Fisette P.L. Anderson R.A. J. Biol. Chem. 1994; 269: 11547-11554Abstract Full Text PDF PubMed Google Scholar). Both enzymes synthesize PI-4,5-P2 in vitro, although by different mechanisms (see below). Isolation and analysis of PIP5KI and PIP5KII cDNA sequences demonstrated that the PIPKs constitute a novel family of kinases (17Boronenkov I.V. Anderson R.A. J. Biol. Chem. 1995; 270: 2881-2884Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar,18Loijens J.C. Anderson R.A. J. Biol. Chem. 1996; 271: 32937-32943Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar). Surprisingly, the PIPKs do not share any statistically significant identity to other known lipid or protein kinases. Known PI 4-kinases and PI 3-kinases share sequence homology over distinct domains, and some of these domains are related to those found in protein kinases (19Carpenter C.L. Cantley L.C. Biochemistry. 1990; 29: 11147-11156Crossref PubMed Scopus (296) Google Scholar, 20Gehrmann T. Heilmeyer L.M.G. Eur. J. Biochem. 1998; 253: 357-370Crossref PubMed Scopus (109) Google Scholar, 21Flanagan C.A. Schnieders E.A. Emerick A.W. Kunisawa R. Admon A. Thorner J. Science. 1993; 262: 1444-1448Crossref PubMed Scopus (171) Google Scholar, 22Garcia-Bustos J.F. Marini F. Stevenson I. Frei C. Hall M.N. EMBO J. 1994; 13: 2352-2361Crossref PubMed Scopus (103) Google Scholar, 23Yoshida S. Ohya Y. Goebl M. Nakano A. Anraku Y. J. Biol. Chem. 1994; 269: 1166-1172Abstract Full Text PDF PubMed Google Scholar, 24Hanks S.K. Hunter T. FASEB J. 1995; 9: 576-596Crossref PubMed Scopus (2296) Google Scholar), suggesting that these enzymes have a similar phosphotransferase mechanism. Initially, the only homologs of PIPKs were the Saccharomyces cerevisiae gene products, Mss4p and Fab1p (17Boronenkov I.V. Anderson R.A. J. Biol. Chem. 1995; 270: 2881-2884Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, 25Yamamoto A. DeWald D.B. Boronenkov I.V. Anderson R.A. Emr S.D. Koshland D. Mol. Biol. Cell. 1995; 6: 525-539Crossref PubMed Scopus (236) Google Scholar, 26Yoshida S. Ohya Y. Nakano A. Anraku Y. Mol. Gen. Genet. 1994; 242: 631-640Crossref PubMed Scopus (77) Google Scholar). Since then, the number of PIPK homologs in the sequence data base has mounted to over 20. PIPKI and PIPKII homologs are now found throughout the animal and plant kingdoms suggesting that their signaling functions are ubiquitous and conserved. In mammalian cells, three isoforms of each PIPKI and PIPKII subfamily, encoded by distinct genes, have been characterized and named α, β, and γ (27Castellino A.M. Parker G.J. Boronenkov I.V. Anderson R.A. Chao M.V. J. Biol. Chem. 1997; 272: 5861-5870Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 28Ishihara H. Shibasaki Y. Kizuki N. Katagiri H. Yazaki Y. Asano T. Oka Y. J. Biol. Chem. 1996; 271: 23611-23614Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 29Ishihara H. Shibasaki Y. Kizuki N. Wada T. Yazaki Y. Asano T. Oka Y. J. Biol. Chem. 1998; 273: 8741-8748Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 30Itoh T. Ijuin T. Takenawa T. J. Biol. Chem. 1998; 273: 20292-20299Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar), and additional PIPKs likely remain to be discovered. The regions of sequence homology are found within the C terminus. The identity between PIPKs can be as low as 27% (17Boronenkov I.V. Anderson R.A. J. Biol. Chem. 1995; 270: 2881-2884Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). However, the regions of sequence identity are clustered, reminiscent of that between diverse protein kinases and phosphatidylinositol 3- and 4-kinases (20Gehrmann T. Heilmeyer L.M.G. Eur. J. Biochem. 1998; 253: 357-370Crossref PubMed Scopus (109) Google Scholar, 24Hanks S.K. Hunter T. FASEB J. 1995; 9: 576-596Crossref PubMed Scopus (2296) Google Scholar). We now know these conserved domains represent the catalytic core of the kinases. The kinase domain, except in Fab1p homologs, is separated by an insert region. Recently, PIPKs in Arabidopsis thaliana have been characterized and based on their sequence appear to form a unique subfamily of enzymes (65Satterlee J.S. Sussman M.R. Plant Physiol. 1998; 115: 864Google Scholar). In Fig.1, the subfamilies of PIPK have been summarized and the regions of identity in the kinase domains aligned and shown as a similarity plot. Although statistically there is no homology with other kinases, there are similarities in the conserved sequence motifs. For example, a glycine-rich motif (GXSGS) in the homologs resembles the phosphate-binding loop of protein kinases and other ATP-binding proteins (24Hanks S.K. Hunter T. FASEB J. 1995; 9: 576-596Crossref PubMed Scopus (2296) Google Scholar, 31Bossemeyer D. Trends Biochem. Sci. 1994; 19: 201-205Abstract Full Text PDF PubMed Scopus (153) Google Scholar). It is also similar to GTP-binding sequences, which is consistent with the ability of PIPKs to use both ATP and GTP as phosphate donors (15Bazenet C.E. Ruano A.R. Brockman J.L. Anderson R.A. J. Biol. Chem. 1990; 265: 18012-18022Abstract Full Text PDF PubMed Google Scholar, 32Staeheli P. Pitossi F. Pavlovic J. Trends Cell Biol. 1993; 3: 268-272Abstract Full Text PDF PubMed Scopus (130) Google Scholar). An invariant lysine (IIK sequence) that is C-terminal of the glycine-rich region resembles the conserved lysine found in protein kinases that binds the α-phosphate of ATP (24Hanks S.K. Hunter T. FASEB J. 1995; 9: 576-596Crossref PubMed Scopus (2296) Google Scholar,25Yamamoto A. DeWald D.B. Boronenkov I.V. Anderson R.A. Emr S.D. Koshland D. Mol. Biol. Cell. 1995; 6: 525-539Crossref PubMed Scopus (236) Google Scholar). The diversity of PIPKs may, in part, be because of their unexpected ability to utilize different substrates and to generate multiple signaling molecules. PIPKI isoforms preferentially phosphorylate PI-4-P to PI-4,5-P2. However, at leastin vitro, they also phosphorylate PI-3-P on both the 4- and 5-hydroxyls forming PI-3,4-P2 and PI-3,5-P2(33Zhang X. Loijens J.C. Boronenkov I.V. Parker G.J. Norris F.A. Chen J. Thum O. Prestwich G.D. Majerus P.W. Anderson R.A. J. Biol. Chem. 1997; 272: 17756-17761Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 34Rameh L.E. Tolias K.F. Duckworth B.C. Cantley L.C. Nature. 1997; 390: 192-196Crossref PubMed Scopus (372) Google Scholar, 35Tolias K.F. Rameh L.E. Ishihara H. Shibasaki Y. Chen J. Prestwich G.D. Cantley L.C. Carpenter C.L. J. Biol. Chem. 1998; 273: 18040-18046Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). In they generate from PI-3-P in a X. Loijens J.C. Boronenkov I.V. Parker G.J. Norris F.A. Chen J. Thum O. Prestwich G.D. Majerus P.W. Anderson R.A. J. Biol. Chem. 1997; 272: 17756-17761Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). PIPKI isoforms phosphorylate PI forming K.F. Rameh L.E. Ishihara H. Shibasaki Y. Chen J. Prestwich G.D. Cantley L.C. Carpenter C.L. J. Biol. Chem. 1998; 273: 18040-18046Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). are kinases phosphorylating the 4- and 5-hydroxyls of of their sequence identity to PIPKII isoforms were to have similar It as a the of PIPKII was identified as PI-4-P L.E. Tolias K.F. Duckworth B.C. Cantley L.C. Nature. 1997; 390: 192-196Crossref PubMed Scopus (372) Google Scholar). The of PI-4,5-P2 (17Boronenkov I.V. Anderson R.A. J. Biol. Chem. 1995; 270: 2881-2884Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, X. Loijens J.C. Boronenkov I.V. Parker G.J. Norris F.A. Chen J. Thum O. Prestwich G.D. Majerus P.W. Anderson R.A. J. Biol. Chem. 1997; 272: 17756-17761Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 34Rameh L.E. Tolias K.F. Duckworth B.C. Cantley L.C. Nature. 1997; 390: 192-196Crossref PubMed Scopus (372) Google Scholar, 35Tolias K.F. Rameh L.E. Ishihara H. Shibasaki Y. Chen J. Prestwich G.D. Cantley L.C. Carpenter C.L. J. Biol. Chem. 1998; 273: 18040-18046Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). The that are PI-4-P 5-kinase to be because of of PI-4-P with and the to from PI-4-P PIPKII isoforms also use PI-3-P as a and the of is in the are 4-kinases and appear to be in their In the in of the PIPKII isoforms is PI-3-P J. C. J. and R. A. the of for characterized PIPKI isoforms is PI-4-P PI-3-P PI-3,4-P2 PI (14Ling L.E. Schulz J.T. Cantley L.C. J. Biol. Chem. 1989; 264: 5080-5088Abstract Full Text PDF PubMed Google Scholar, 15Bazenet C.E. Ruano A.R. Brockman J.L. Anderson R.A. J. Biol. Chem. 1990; 265: 18012-18022Abstract Full Text PDF PubMed Google Scholar, 16Jenkins G.H. Fisette P.L. Anderson R.A. J. Biol. Chem. 1994; 269: 11547-11554Abstract Full Text PDF PubMed Google Scholar, I.V. Anderson R.A. J. Biol. Chem. 1995; 270: 2881-2884Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, J.C. Anderson R.A. J. Biol. Chem. 1996; 271: 32937-32943Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, X. Loijens J.C. Boronenkov I.V. Parker G.J. Norris F.A. Chen J. Thum O. Prestwich G.D. Majerus P.W. Anderson R.A. J. Biol. Chem. 1997; 272: 17756-17761Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 34Rameh L.E. Tolias K.F. Duckworth B.C. Cantley L.C. Nature. 1997; 390: 192-196Crossref PubMed Scopus (372) Google Scholar, 35Tolias K.F. Rameh L.E. Ishihara H. Shibasaki Y. Chen J. Prestwich G.D. Cantley L.C. Carpenter C.L. J. Biol. Chem. 1998; 273: 18040-18046Abstract Full Text Full Text PDF PubMed Scopus Google Scholar, S.K. M.R. Parker Nature. 1997; 390: PubMed Scopus Google Scholar, S. M. H. Anraku Y. Y. Ohya Y. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, S. Parker Hall M.N. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). The of messengers and substrates by kinases in is these activities PIPKs as in the of known signaling molecules. kinase activities are and the of any family of An that the in activities of PIPKs their in functions is the that and have been recently identified in cells L.E. Tolias K.F. Duckworth B.C. Cantley L.C. Nature. 1997; 390: 192-196Crossref PubMed Scopus (372) Google Scholar, S.K. M.R. Parker Nature. 1997; 390: PubMed Scopus Google Scholar). However, in both the of of these novel to be In data that PIPKI isoforms synthesize from PI K.F. Rameh L.E. Ishihara H. Shibasaki Y. Chen J. Prestwich G.D. Cantley L.C. Carpenter C.L. J. Biol. Chem. 1998; 273: 18040-18046Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). PIPKI for the low of in or an as kinase or is in is Recently, S.K. M.R. Parker Nature. 1997; 390: PubMed Scopus Google demonstrated that is in both and mammalian cells in to Mss4p is to only PI-4,5-P2 and PI-3,4-P2 S. M. H. Anraku Y. Y. Ohya Y. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, S. Parker Hall M.N. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). the only other PIPK in is likely for (see below). Recently, the of the first has been S. I.V. Anderson R.A. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The of of that at the This is consistent with the of the protein in (14Ling L.E. Schulz J.T. Cantley L.C. J. Biol. Chem. 1989; 264: 5080-5088Abstract Full Text PDF PubMed Google Scholar, 15Bazenet C.E. Ruano A.R. Brockman J.L. Anderson R.A. J. Biol. Chem. 1990; 265: 18012-18022Abstract Full Text PDF PubMed Google Scholar, S. I.V. Anderson R.A. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). the a of and to form a The at the form a that the to the C of the although the are the is an of is and with a of S. I.V. Anderson R.A. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The and the that region functions as an for the was a This demonstrated that the region the the suggesting that only are in The of is by of the catalytic at the Although the PIPKs are not statistically to protein kinases, the a region of acid in each subunit of the that be on the ATP and catalytic of protein kinase S. I.V. Anderson R.A. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). catalytic are conserved for PIPKs and have in protein kinases, the and of and S.K. M.R. Parker Nature. 1997; 390: PubMed Scopus Google Scholar). The in protein kinase are and Science. 253: PubMed Scopus Google Scholar). The conserved lysine in with the α-phosphate of ATP binds or Science. 253: PubMed Scopus Google Scholar). to have a in base of in protein kinases and is also the is in in is in the motif conserved in protein kinases. The PIPKs a similar conserved the that been as a A. DeWald D.B. Boronenkov I.V. Anderson R.A. Emr S.D. Koshland D. Mol. Biol. Cell. 1995; 6: 525-539Crossref PubMed Scopus (236) Google Scholar). Although of in the the of demonstrated that these are not The of the in the is in the The of the in protein kinases is in the PIPKs have a glycine-rich loop or with the sequence of This region to the loop of protein kinases. In both kinase loop that their with the phosphate of as a The of ATP the of that the a conserved in each The phosphate is to with the and and the is the The of was by and ATP the In the with a of conserved in a The of the catalytic that the can that PI-3-P or the consistent with the of the kinases. In both the of in with the loop in the was to as the because it to the loop in protein kinases and PI kinases (20Gehrmann T. Heilmeyer L.M.G. Eur. J. Biochem. 1998; 253: 357-370Crossref PubMed Scopus (109) Google Scholar, S. I.V. Anderson R.A. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). This loop is on each of the and has the to the and both kinase and the of the and the of the to that the PIPKII was to phosphorylate substrates at the of the phosphoinositide signaling enzymes directly with the characterized are with kinase (6Rana R.S. Hokin L.E. Physiol. Rev. 1990; 70: 115-164Crossref PubMed Scopus (431) Google Scholar, 7Lee S.B. Rhee S.G. Curr. Opin. Cell Biol. 1995; 7: 183-189Crossref PubMed Scopus (284) Google Scholar, 8Rhee S.G. Bae Y.S. J. Biol. Chem. 1997; 272: 15045-15048Crossref PubMed Scopus (817) Google Scholar, 9Nishizuka Y. FASEB J. 1995; 9: 484-496Crossref PubMed Scopus (2368) Google Scholar, K.R. Serunian L.A. Soltoff S.P. Libby P. Cantley L.C. Cell. 1989; 57: 167-175Abstract Full Text PDF PubMed Scopus (684) Google Scholar, 11Stephens L.R. Jackson T.R. Hawkins P.T. Biochim. Biophys. Acta. 1993; 1179: 27-75Crossref PubMed Scopus (426) Google Scholar, 12Toker A. Cantley L.C. Nature. 1997; 387: 673-676Crossref PubMed Scopus (1229) Google Scholar, 13Downward J. Curr. Opin. Cell Biol. 1998; 10: 262-267Crossref PubMed Scopus (1190) Google Scholar). signaling enzymes isoforms of PI and phospholipase C. at with and their activities are to of C family utilize PI-4,5-P2 for second PI-4,5-P2 is also to be a for the PI 3-kinases L.R. Jackson T.R. Hawkins P.T. Biochim. Biophys. Acta. 1993; 1179: 27-75Crossref PubMed Scopus (426) Google Scholar), PI-3,4-P2 can be by the of P.W. M.V. Norris F.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). also with (see the in P.W. M.V. Norris F.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google there is also that PIPKs directly with the tumor necrosis factor and the epidermal growth factor (27Castellino A.M. Parker G.J. Boronenkov I.V. Anderson R.A. Chao M.V. J. Biol. Chem. 1997; 272: 5861-5870Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, C. O. Hunter T. J. Biol. Chem. Full Text PDF PubMed Google Scholar). In the of the only with the the not (27Castellino A.M. Parker G.J. Boronenkov I.V. Anderson R.A. Chao M.V. J. Biol. Chem. 1997; 272: 5861-5870Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). The is to with both PI and 5-kinase activities, although the kinase isoforms have not been C. O. Hunter T. J. Biol. Chem. Full Text PDF PubMed Google Scholar). both the and with PIPKs their domains within sequences of from the the The on for is within the to the The with and of The of these to be these signaling enzymes are likely to to second or of In there is also for of a PI-3-P by and protein kinase C Biochem. Biophys. 1990; PubMed Scopus Google Scholar, A. Carpenter C. Cantley L.C. J. Biol. Chem. 1990; 265: Full Text PDF PubMed Google Scholar). is in and as the only identified PI-3-P in is a for that PI-3-P N. O. Biochem. J. 1995; PubMed Scopus Google Scholar, N. EMBO J. 1996; PubMed Scopus Google Scholar). there is that the PIPKII the can be in to T. Ijuin T. Takenawa T. J. Biol. Chem. 1998; 273: 20292-20299Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). signaling has been in and and has been recently P. Emr S.D. P. Science. 1996; 271: PubMed Scopus Google Scholar). Fab1p was the first PIPK to have an in (17Boronenkov I.V. Anderson R.A. J. Biol. Chem. 1995; 270: 2881-2884Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, 25Yamamoto A. DeWald D.B. Boronenkov I.V. Anderson R.A. Emr S.D. Koshland D. Mol. Biol. Cell. 1995; 6: 525-539Crossref PubMed Scopus (236) Google Scholar). or of Fab1p in of and cells and a in and A. DeWald D.B. Boronenkov I.V. Anderson R.A. Emr S.D. Koshland D. Mol. Biol. Cell. 1995; 6: 525-539Crossref PubMed Scopus (236) Google Scholar). The is by that the other appear to be Recently, a has between the only PI and it is for protein to the Emr S.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). were the of was and was S.K. M.R. Parker Nature. 1997; 390: PubMed Scopus Google Scholar). PI-3-P by is likely a for a and the likely is Fab1p in and share some of the of Fab1p form a with to synthesize the second in Emr S.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google for PIPK and PI-4,5-P2 has been for J.C. Fisette P.L. G.H. Takenawa T. Anderson R.A. Nature. 1995; PubMed Scopus Google Scholar). The that PIPK is the This is for the of The PIPKs for ATP were for PIPKI In of the of the in not be The enzymes that are in have at in by phosphatidic acid G.H. Fisette P.L. Anderson R.A. J. Biol. Chem. 1994; 269: 11547-11554Abstract Full Text PDF PubMed Google Scholar, 28Ishihara H. Shibasaki Y. Kizuki N. Katagiri H. Yazaki Y. Asano T. Oka Y. J. Biol. Chem. 1996; 271: 23611-23614Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 29Ishihara H. Shibasaki Y. Kizuki N. Wada T. Yazaki Y. Asano T. Oka Y. J. Biol. Chem. 1998; 273: 8741-8748Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). D which has also been in and Curr. Opin. Cell Biol. 1997; 9: PubMed Scopus Google Scholar). In mammalian PI-4,5-P2 for S. C. Cell. 1993; Full Text PDF Scopus Google Scholar). the PIPKI enzymes be by and the PIP2 This in a loop that generate both and PIP2 at within In the of the PIP2 and be to the In other signaling the of and be and to other functions as For has that PI-4,5-P2 can the of proteins which the or of in Rev. Physiol. 1994; PubMed Scopus Google Scholar). Recently, it was that of PIPKI isoforms in cells of in Y. Ishihara H. Kizuki N. Asano T. Oka Y. Yazaki Y. J. Biol. Chem. 1997; 272: PubMed Scopus (153) Google Scholar). However, a of the PIPKI which also H. Shibasaki Y. Kizuki N. Wada T. Yazaki Y. Asano T. Oka Y. J. Biol. Chem. 1998; 273: 8741-8748Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). a there some as to or not is for PIPKI of in the PIPKs by of PIP2 of PI-4,5-P2 to be and PIPKI is for of a for and is also of is by many that also in is by the Hall A. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). and Hall A. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google and have also been to or with PIPKI isoforms A. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar, A. G.H. Anderson R.A. Mol. Biol. Cell. 1996; 7: PubMed Scopus Google Scholar, K.F. Cantley L.C. Carpenter C.L. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, K.F. Cantley L.C. Carpenter C.L. Mol. Cell. Biol. 1998; 18: PubMed Scopus Google Scholar). the for a of between the PIPKs and other signaling molecules that in The PIPK is for in S.K. M.R. Parker Nature. 1997; 390: PubMed Scopus Google Scholar, S. M. H. Anraku Y. Y. Ohya Y. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). Mss4p do not have the ability to form and to their of a growth and S.K. M.R. Parker Nature. 1997; 390: PubMed Scopus Google Scholar). Mss4p are by a PIPKI and the properties of are similar to PIPKI isoforms S. M. H. Anraku Y. Y. Ohya Y. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). PI signaling pathways are based at the and to by However, a distinct PI in the and is from the PI (see for review N. H. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar). the of these signaling pathways has been that a of the enzymes and phosphoinositides are in that have been of their with M. J. M. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The is that the enzymes and phosphoinositides are not with within the PIPKI and PIPKII isoforms are in to that are separated from known I.V. Loijens J.C. Anderson R.A. Mol. Cell. Biol. 1998; 9: Scopus Google Scholar). also enzymes for and are to suggesting that the PIPKs generate PIP2 in I.V. Loijens J.C. Anderson R.A. Mol. Cell. Biol. 1998; 9: Scopus Google Scholar). are and their is to the of of these to and in the PIPKs and PIP2 Although the of the PIPKs at is not is additional for of the PIPKs that are to by the messengers that they is also for the of kinase to M. Nature. 1998; PubMed Scopus Google Scholar). by kinase PIPKI combined data a of the PIPKs in cells at the in on or within The in data that PIPK are suggesting that the PIPK family generate all of signaling the for substrates and the of different products by these kinases be by which to PIPK is to phosphoinositide substrates to these kinases. This by both PI and PIPKs a or within a In PI kinases synthesize a which be a for the PIPKs PI-4,5-P2 within cells are to not it is to of PI-4,5-P2 can be in The that PIPKs within cells and that the and of PI-4,5-P2 at these or is and to also at these PIP2 at not within a the the that can be