p85 Associates with unphosphorylated PTEN and the PTEN-associated complex.
The lipid phosphatase PTEN functions as a tumor suppressor by dephosphorylating the D3 position of phosphoinositide-3,4,5-trisphosphate, thereby negatively regulating the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. In mammalian cells, PTEN exists either as a monomer or as a part of a >600-kDa complex (the PTEN-associated complex [PAC]). Previous studies suggest that the antagonism of PI3K/AKT signaling by PTEN may be mediated by a nonphosphorylated form of the protein resident within the multiprotein complex. Here we show that PTEN associates with p85, the regulatory subunit of PI3K. Using newly generated antibodies, we demonstrate that this PTEN-p85 association involves the unphosphorylated form of PTEN engaged within the PAC and also includes the p110beta isoform of PI3K. The PTEN-p85 association is enhanced by trastuzumab treatment and linked to a decline in AKT phosphorylation in some ERBB2-amplified breast cancer cell lines. Together, these results suggest that integration of p85 into the PAC may provide a novel means of downregulating the PI3K/AKT pathway.
Rabinovsky
Rosalia
R
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115, USA.
Pochanard
Panisa
P
McNear
Chontelle
C
Brachmann
Saskia M
SM
Duke-Cohan
Jonathan S
JS
Garraway
Levi A
LA
Sellers
William R
WR
D000595:Amino Acid Sequence; D000906:Antibodies / Q000276:immunology; D002460:Cell Line; D006801:Humans; D008969:Molecular Sequence Data; D008970:Molecular Weight; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology
D000906:Antibodies; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D021122:Protein Subunits; D018719:Erb-b2 Receptor Tyrosine Kinases; C494929:PTEN protein, human