PTEN is a tumor suppressor protein and mutations in its gene have been found in a variety of human cancers and in cancer predisposition syndromes. At the molecular level, recent studies suggest that PTEN is a phosphatase for phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 is produced by phosphatidylinositol 3-kinase (PI 3-kinase). We have previously shown that in C. elegans, the PTEN homolog DAF-18 functions as a negative regulator for the signaling pathway controlled by DAF-2, an insulin receptor-like molecule and by AGE-1, a PI 3-kinase homolog (1). We have established that a deletion mutation in the catalytic domain of CePTEN/DAF-18,
daf-18(
nr2037), completely suppresses the dauer-constitutive phenotype caused by mutations in
daf-2 or in
age-1. In addition, we have demonstrated that
daf-18(
nr2037) mutant dramatically shortens life-span, both in a wild-type strain background and in a
daf-2 mutant background that normally prolongs life-span. The fact that inactivation of
daf-18 suppresses the null mutation in
age-1 PI 3-kinase suggest that there may be other enzymes involved in the production of PIP3 in a mutant strain that lacks AGE-1 activity. In the C. elegans genome database, we found that there is a type II PI 3-kinase homolog encoded by the F39B1.1 locus. AGE-1 belongs to the type I PI 3-kinase subfamily. While the type I PI 3-kinases are known to be activated by association with the growth factor receptor tyrosine kinases, very little is known about the function and regulation of the type II PI 3-kinases. To determine if the type II PI 3-kinase homolog in C. elegans is involved in generating PIP3, we undertook the approach of the reverse genetics and obtained a mutant strain that carries a deletion in the F39B1.1 gene. We are in the process of characterizing this mutant and determining the functional relationship of this gene with
age-1 and
daf-18/CePTEN in regulation of dauer formation and life-span processes. 1. V. Mihaylova, C. Borland, L. Manjarrez, M. Stern and H. Sun (1999) Proc. Natl. Acad. Sci. USA 96, 7427-7432.