A novel phosphatidylinositol(3,4,5)P3 pathway in fission yeast.
The mammalian tumor suppressor, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), inhibits cell growth and survival by dephosphorylating phosphatidylinositol-(3,4,5)-trisphosphate (PI[3,4,5]P3). We have found a homologue of PTEN in the fission yeast, Schizosaccharomyces pombe (ptn1). This was an unexpected finding because yeast (S. pombe and Saccharomyces cerevisiae) lack the class I phosphoinositide 3-kinases that generate PI(3,4,5)P3 in higher eukaryotes. Indeed, PI(3,4,5)P3 has not been detected in yeast. Surprisingly, upon deletion of ptn1 in S. pombe, PI(3,4,5)P3 became detectable at levels comparable to those in mammalian cells, indicating that a pathway exists for synthesis of this lipid and that the S. pombe ptn1, like mammalian PTEN, suppresses PI(3,4,5)P3 levels. By examining various mutants, we show that synthesis of PI(3,4,5)P3 in S. pombe requires the class III phosphoinositide 3-kinase, vps34p, and the phosphatidylinositol-4-phosphate 5-kinase, its3p, but does not require the phosphatidylinositol-3-phosphate 5-kinase, fab1p. These studies suggest that a pathway for PI(3,4,5)P3 synthesis downstream of a class III phosphoinositide 3-kinase evolved before the appearance of class I phosphoinositide 3-kinases.
Mitra
Prasenjit
P
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St., Rm. 819, Worcester, MA 01605, USA.
Zhang
Yingjie
Y
Rameh
Lucia E
LE
Ivshina
Maria P
MP
McCollum
Dannel
D
Nunnari
John J
JJ
Hendricks
Gregory M
GM
Kerr
Monica L
ML
Field
Seth J
SJ
Cantley
Lewis C
LC
Ross
Alonzo H
AH
D019143:Evolution, Molecular; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D012568:Schizosaccharomyces / Q000166:cytology / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D029702:Schizosaccharomyces pombe Proteins
D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D010744:Phosphoric Monoester Hydrolases; D017853:Phosphotransferases (Alcohol Group Acceptor); D029701:Saccharomyces cerevisiae Proteins; D029702:Schizosaccharomyces pombe Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; C095504:FAB1 protein, S cerevisiae; C020077:1-phosphatidylinositol-4-phosphate 5-kinase