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Volume 272, Number 20, Issue of May 16, 1997 pp. 13033-13039
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Interactions between Protein Kinase C and Pleckstrin Homology Domains
INHIBITION BY PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE AND PHORBOL 12-MYRISTATE 13-ACETATE

(Received for publication, December 31, 1996, and in revised form, March 4, 1997)

Libo Yao , Hidefumi Suzuki , Koichiro Ozawa , Jianbei Deng , Csaba Lehel ^¶ , Hiromi Fukamachi , Wayne B. Anderson ^¶ , Yuko Kawakami and Toshiaki Kawakami

From the Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, the  Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Takasaki, Gunma 370-12, Japan, and the ^¶ Laboratory of Cellular Oncology, NCI, National Institutes of Health, Bethesda, Maryland 20892

Pleckstrin homology (PH) domains comprised of loosely conserved sequences of ~100 amino acid residues are a functional protein motif found in many signal-transducing and cytoskeletal proteins. We recently demonstrated that the PH domains of Tec family protein-tyrosine kinases Btk and Emt (equal to Itk and Tsk) interact with protein kinase C (PKC) and that PKC down-regulates Btk by phosphorylation. In this study we have characterized the PKC-BtkPH domain interaction in detail. Using pure PKC preparations, it was shown that the Btk PH domain interacts with PKC with high affinity (K_D = 39 nM). Unlike other tested phospholipids, phosphatidylinositol 4,5-bisphosphate, which binds to several PH domains, competed with PKC for binding to the PH domain apparently because their binding sites on the amino-terminal portion of the PH domains overlap. The minimal PKC-binding sequence within the Btk PH domain was found to correspond roughly to the second and third -sheets of the PH domains of known tertiary structures. On the other hand, the C1 regulatory region of PKC containing the pseudosubstrate and zinc finger-like sequences was found to be sufficient for strong binding to the Btk PH domain. Phorbol 12-myristate 13-acetate (PMA), a potent activator of PKC that interacts with the C1 region of PKC, inhibited the PKC-PH domain interaction, whereas the bioinactive PMA (4--PMA) was ineffective. The  isoform of PKC, which has a single zinc finger-like motif instead of the two tandem zinc finger-like sequences present in conventional and novel PKC isoforms, does not bind PMA. Thus, as expected, PH domain binding with PKC was not interfered with by PMA. Further, inhibitors that are known to attack the catalytic domains of serine/threonine kinases did not affect this PKC-PH domain interaction. In contrast, the presence of physiological concentrations of Ca²⁺ induced less than a 2-fold increase in PKC-PH domain binding. These results indicate that PKC binding to PH domains involve the 2-3 region of the Btk PH domain and the C1 region of PKC, and agents that interact with either of these regions (i.e. phosphatidylinositol 4,5-bisphosphate binding to the PH domain and PMA binding to the C1 region of PKC) might act to regulate PKC-PH domain binding.

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