Volume 272, Number 17, Issue of April 25, 1997 pp. 11096-11102
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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Structure-Function Studies of p38 Mitogen-activated Protein Kinase
LOOP 12 INFLUENCES SUBSTRATE SPECIFICITY AND AUTOPHOSPHORYLATION, BUT NOT UPSTREAM KINASE SELECTION

(Received for publication, January 23, 1997)

Yong Jiang , Zhuangjie Li , Edward M. Schwarz ^§ , Anning Lin ^¶ , Kunliang Guan , Richard J. Ulevitch and Jiahuai Han

From the  Department of Immunology, Scripps Research Institute and the ^§ Laboratory of Genetics, Salk Institute, La Jolla, California 92037, the ^¶ Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, and the  Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109

Several mitogen-activated protein kinase (MAPK) cascades have been identified in eukaryotic cells. The activation of MAPKs is carried out by distinct MAPK kinases (MEKs or MKKs), and individual MAPKs have different substrate preferences. Here we have examined how amino acid sequences encompassing the dual phosphorylation motif located in the loop 12 linker (L12) between kinase subdomains VII and VIII and the length and amino acid sequence of L12 influence autophosphorylation, substrate specificity, and upstream kinase selectivity for the MAPK p38. Conversion of L12 of p38 to an "ERK-like" structure was accomplished in several ways: (i) by replacing glycine with glutamate in the dual phosphorylation site, (ii) by placing a six-amino acid sequence present in L12 of ERK (but absent in p38) into p38, and (iii) by mutations of amino acid residues in loop 12. Two predominant effects were noted: (i) the Xaa residue in the dual phosphorylation motif Thr-Xaa-Tyr as well as the length of L12 influence p38 substrate specificity, and (ii) the length of L12 plays a major role in controlling autophosphorylation. In contrast, these modifications do not result in any change in the selection of p38 by individual MAPK kinases.

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