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Molecular and Cellular Biology, July 1999, p. 4643-4652, Vol. 19, No. 7
Department of Molecular Biology, Lerner
Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
44195,1 and Tularik, Incorporated, South
San Francisco, California 940802
Received 25 November 1998/Returned for modification 28 January
1999/Accepted 22 March 1999
Mutagenized human 293 cells containing an interleukin-1
(IL-1)-regulated herpes thymidine kinase gene, selected in IL-1 and gancyclovir, have yielded many independent clones that are unresponsive to IL-1. The four clones analyzed here carry recessive mutations and
represent three complementation groups. Mutant A in complementation group I1 lacks IL-1 receptor-associated kinase (IRAK), while the mutants in the other two groups are defective in unknown components that function upstream of IRAK. Expression of exogenous IRAK in I1A
cells (I1A-IRAK) restores their responsiveness to IL-1. Neither NF
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Mutant Cells That Do Not Respond to Interleukin-1 (IL-1) Reveal a
Novel Role for IL-1 Receptor-Associated Kinase
B
nor Jun kinase is activated in IL-1-treated I1A cells, but these
responses are restored in I1A-IRAK cells, indicating that IRAK is
required for both. To address the role of the kinase activity of IRAK
in IL-1 signaling, its ATP binding site was mutated (K239A), completely
abolishing kinase activity. In transfected I1A cells, IRAK-K239A was
still phosphorylated upon IL-1 stimulation and, surprisingly, still
complemented all the defects in the mutant cells. Therefore, IRAK must
be phosphorylated by a different kinase, and phospho-IRAK must play a
role in IL-1-mediated signaling that does not require its kinase activity.
*
Corresponding author. Mailing address: Lerner Research
Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave.,
Cleveland, OH 44195. Phone: (216) 444-3900. Fax: (216) 444-3279. E-mail
address: starkg{at}cesmtp.ccf.org.
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