title: Ionizing radiation stimulates a Grb2-mediated association of the stress-activated protein kinase with phosphatidylinositol 3-kinase.
abstract: The stress-activated protein (SAP) kinases are induced by tumor necrosis factor, oncoproteins, and UV light. The present studies demonstrate that ionizing radiation (IR) activates p54 SAP kinase. IR-induced activation of SAP kinase is associated with binding to the SH2/SH3-containing adaptor protein Grb2. This interaction is mediated by the SH3 domains of Grb2 and the proline-rich sequence PPPKIP in the carboxy-terminal region of SAP kinase. We also demonstrated that SAP kinase and the p85 alpha-subunit of phosphatidylinositol (PI) 3-kinase form a complex in irradiated cells. The results indicate that this complex involves binding of the p85 alpha subunit of PI 3-kinase to the SH2 domain of Grb2. The functional role of linking SAP kinase to PI 3-kinase is further supported by the finding that wortmannin, an inhibitor of PI 3-kinase, stimulates SAP kinase activity. These results suggest that the cellular response to IR may include regulation of SAP kinase by a PI 3-kinase-dependent signaling pathway.
authors.affiliation: Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kharbanda
authors.forename: A
authors.initials: A
authors.lastname: Saleem
authors.forename: T
authors.initials: T
authors.lastname: Shafman
authors.forename: Y
authors.initials: Y
authors.lastname: Emoto
authors.forename: N
authors.initials: N
authors.lastname: Taneja
authors.forename: E
authors.initials: E
authors.lastname: Rubin
authors.forename: R
authors.initials: R
authors.lastname: Weichselbaum
authors.forename: J
authors.initials: J
authors.lastname: Woodgett
authors.forename: J
authors.initials: J
authors.lastname: Avruch
authors.forename: J
authors.initials: J
authors.lastname: Kyriakis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000528:radiation effects*; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011506:Proteins / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D011506:Proteins; D014801:Vitamin A; C095154:13,14-dihydroxyretinol; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases