Ionizing radiation stimulates a Grb2-mediated association of the stress-activated protein kinase with phosphatidylinositol 3-kinase.
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.
Kharbanda
S
S
Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Saleem
A
A
Shafman
T
T
Emoto
Y
Y
Taneja
N
N
Rubin
E
E
Weichselbaum
R
R
Woodgett
J
J
Avruch
J
J
Kyriakis
J
J
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
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