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Volume 271, Number 35, Issue of August 30, 1996 pp. 21542-21548
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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A Unique Phosphorylation-dependent Mechanism for the Activation of Ca²⁺/Calmodulin-dependent Protein Kinase Type IV/GR

(Received for publication, April 23, 1996, and in revised form, June 19, 1996)

Talal Chatila , Kristin A. Anderson ^¶ , Nga Ho and Anthony R. Means ^¶

From the  Division of Immunology/Rheumatology, Department of Pediatrics, Washington University School of Medicine, St. Louis Missouri 63110 and the ^¶ Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710

The activity of the Ca²⁺/calmodulin-dependent protein kinase IV/Gr (CaMKIV/Gr) is shown to be strictly regulated by phosphorylation of three residues both in vitro and in response to antigen receptor-mediated signaling in lymphocytes. One residue, Thr-200, is indispensable for enhancement of Ca²⁺/calmodulin-dependent basal activity by CaMKIV/Gr kinase. This event requires Ca²⁺/calmodulin in the full-length CaMKIV/Gr but is Ca²⁺/calmodulin-independent when a truncated version of CaMKIV/Gr is used as a substrate (CaMKIV/Gr_1-317 (1-317)). The other two residues, Ser¹² and Ser¹³, are apparently autophosphorylated by the Ca²⁺/calmodulin-bound CaMKIV/Gr. Phosphorylation of neither Ser¹²-Ser¹³ nor Thr³¹² (the residue in a homologous position to Thr²⁸⁶ of CaMKII influences the development of Ca²⁺/calmodulin-independent activity or any other property of CaMKIV/Gr examined. Similarly, removal of the NH₂-terminal 20 amino acids has no effect on the activation or function of CaMKIV/Gr. However, mutation of both Ser¹² and Ser¹³ residues to Ala in 1-317 completely abrogates activity, while individual substitutions have no effect. These results indicate that the NH₂-terminal Ser cluster mediates a novel type of intrasteric inhibition and suggest that three events are required for CaMKIV/Gr activation: 1) Ca²⁺/calmodulin binding; 2) phosphorylation of the Ca²⁺/calmodulin-bound enzyme on Thr²⁰⁰ by a Ca²⁺/calmodulin-dependent protein kinase kinase; and 3) autophosphorylation of Ser¹²-Ser¹³. This three-step requirement is unique among the multifunctional Ca²⁺/calmodulin-dependent kinases.

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