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Molecular and Cellular Biology, March 2005, p. 2364-2383, Vol. 25, No. 6
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.6.2364-2383.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Activation of Hematopoietic Progenitor Kinase 1 Involves Relocation, Autophosphorylation, and Transphosphorylation by Protein Kinase D1

Rüdiger Arnold,1,2 Irene M. Patzak,3 Brit Neuhaus,3 Sadia Vancauwenbergh,4 André Veillette,5 Johan Van Lint,4* and Friedemann Kiefer3*

Max Planck Institute for Molecular Biomedicine, Münster,1 Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg,2 Max Planck Institute for Physiological and Clinical Research, Bad Nauheim Germany,3 Division of Biochemistry, Katholieke Universiteit Leuven, Leuven, Belgium,4 IRCM, Montreal, Quebec, Canada5

Received 14 June 2004/ Returned for modification 23 July 2004/ Accepted 16 December 2004

Adaptive immune signaling can be coupled to stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) and NF-{kappa}B activation by the hematopoietic progenitor kinase 1 (HPK1), a mammalian hematopoiesis-specific Ste20 kinase. To gain insight into the regulation of leukocyte signal transduction, we investigated the molecular details of HPK1 activation. Here we demonstrate the capacity of the Src family kinase Lck and the SLP-76 family adaptor protein Clnk (cytokine-dependent hematopoietic cell linker) to induce HPK1 tyrosine phosphorylation and relocation to the plasma membrane, which in lymphocytes results in recruitment of HPK1 to the contact site of antigen-presenting cell (APC)-T-cell conjugates. Relocation and clustering of HPK1 cause its enzymatic activation, which is accompanied by phosphorylation of regulatory sites in the HPK1 kinase activation loop. We show that full activation of HPK1 is dependent on autophosphorylation of threonine 165 and phosphorylation of serine 171, which is a target site for protein kinase D (PKD) in vitro. Upon T-cell receptor stimulation, PKD robustly augments HPK1 kinase activity in Jurkat T cells and enhances HPK1-driven SAPK/JNK and NF-{kappa}B activation; conversely, antisense down-regulation of PKD results in reduced HPK1 activity. Thus, activation of major lymphocyte signaling pathways via HPK1 involves (i) relocation, (ii) autophosphorylation, and (iii) transphosphorylation of HPK1 by PKD.

* Corresponding author. Mailing address for Friedemann Kiefer: Max Planck Institute for Molecular Biomedicine, Von-Esmarch-Strasse 56, D-48149 Münster, Germany. Phone: 49 251 835 7181. Fax: 49 251 835 8616. E-mail: fkiefer{at}gwdg.de. Mailing address for Johan Van Lint: Division of Biochemistry, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium. Phone: 32 16 347171. Fax: 32 16 345995. E-mail: Johan.VanLint{at}med.kuleuven.ac.be.

Molecular and Cellular Biology, March 2005, p. 2364-2383, Vol. 25, No. 6
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.6.2364-2383.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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