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Molecular and Cellular Biology, June 2005, p. 4924-4933, Vol. 25, No. 12
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.12.4924-4933.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Intramolecular Regulatory Switch in ZAP-70: Analogy with Receptor Tyrosine Kinases

Tomas Brdicka,1,2,{dagger} Theresa A. Kadlecek,1,{dagger} Jeroen P. Roose,1 Alexander W. Pastuszak,1 and Arthur Weiss1*

Department of Medicine, The Rosalind Russell Medical Research Center for Arthritis, and Howard Hughes Medical Institute, University of California, San Francisco, California 94143,1 Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 Prague, Czech Republic2

Received 5 January 2005/ Returned for modification 25 January 2005/ Accepted 27 March 2005

ZAP-70, a Syk family cytoplasmic protein tyrosine kinase (PTK), is required to couple the activated T-cell antigen receptor (TCR) to downstream signaling pathways. It contains two tandem SH2 domains that bind to phosphorylated TCR subunits and a C-terminal catalytic domain. The region connecting the SH2 domains with the kinase domain, termed interdomain B, has previously been shown to have striking regulatory effects on ZAP-70 function, presumed to be due to the recruitment of key substrates. Paradoxically, deletion of interdomain B preserves ZAP-70 function. Recent structural studies of several receptor tyrosine kinases (RTKs) revealed that their juxtamembrane regions negatively regulate their catalytic activities. In EphB2 and several other RTKs, this autoinhibition depends upon interaction between the kinase domain and tyrosine residues within the juxtamembrane region. Autoinhibition is released when these tyrosines become phosphorylated following receptor stimulation. Sequence homology suggested analogous regulation for ZAP-70. Based on mutagenesis analysis of ZAP-70 interdomain B, we find that this region downregulates ZAP-70 catalytic activity in a similar manner as the juxtamembrane region of EphB2. Similar regulation was also noted for the related Syk kinase. These findings suggest that a general autoinhibitory mechanism employed by RTKs is also used by some cytoplasmic tyrosine kinases.

* Corresponding author. Mailing address: Department of Medicine and Howard Hughes Medical Institute, University of California at San Francisco, 533 Parnassus Avenue, San Francisco, CA 94143-0795. Phone: (415) 476-1291. Fax: (415) 502-5081. E-mail: aweiss{at}medicine.ucsf.edu.

{dagger} T.B. and T.A.K. contributed equally to this work.

Molecular and Cellular Biology, June 2005, p. 4924-4933, Vol. 25, No. 12
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.12.4924-4933.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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