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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.
Highlights
The stress-activated protein (SAP) kinases are induced by tumor necrosis factor, oncoproteins, and UV light
ionizing radiation (IR)-induced stimulation of Jun kinase activity was comparable with that obtained in tumor necrosis factor- (Fig. lA) or sphingomyelinase-treated cells
In order to determine whether the IR-induced Jun kinase activity is due to stimulation of SAP kinase, we assayed anti-p54 SAP kinase immunoprecipitates for phosphorylation of GST-Jun
Summary
The stress-activated protein (SAP) kinases are induced by tumor necrosis factor, oncoproteins, and UV light. After preclearing of the cell lysates, the supernatant was incubated with preimmune rabbit serum, anti-p54 SAP kinase, or anti-Grb2 for 1 h at 4 "C and for 30 min after the addition of protein A-Sepharose. The fusion proteins were incubated with lysates from control and irradiated cells, and the adsorbates were analyzed by immunoblotting with anti-SAP kinase antibody.
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