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Molecular and Cellular Biology, February 1999, p. 1359-1368, Vol. 19, No. 2
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Interaction of Hematopoietic Progenitor Kinase 1 with Adapter Proteins Crk and CrkL Leads to Synergistic Activation of c-Jun N-Terminal Kinase

Pin Ling,1 Zhengbin Yao,2 Christian F. Meyer,1 Xuhong Sunny Wang,2 Wolf Oehrl,3 Stephan M. Feller,3 and Tse-Hua Tan1,*

Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 770301; Department of Biology, Amgen, Inc., Boulder, Colorado 913202; and Laboratory of Molecular Oncology, Institute for Medical Radiation and Cell Research (MSZ), Bavarian Julius-Maximilians University, 97078 Würzburg, Germany3

Received 9 July 1998/Returned for modification 18 August 1998/Accepted 28 October 1998

Hematopoietic progenitor kinase 1 (HPK1), a mammalian Ste20-related protein kinase, is an upstream activator of c-Jun N-terminal kinase (JNK). In order to further characterize the HPK1-mediated JNK signaling cascade, we searched for HPK1-interacting proteins that could regulate HPK1. We found that HPK1 interacted with Crk and CrkL adaptor proteins in vitro and in vivo and that the proline-rich motifs within HPK1 were involved in the differential interaction of HPK1 with the Crk proteins and Grb2. Crk and CrkL not only activated HPK1 but also synergized with HPK1 in the activation of JNK. The HPK1 mutant (HPK1-PR), which encodes the proline-rich region alone, blocked JNK activation by Crk and CrkL. Dominant-negative mutants of HPK1 downstream effectors, including MEKK1, TAK1, and SEK1, also inhibited Crk-induced JNK activation. These results suggest that the Crk proteins serve as upstream regulators of HPK1. We further observed that the HPK1 mutant HPK1-KD(M46), which encodes the kinase domain with a point mutation at lysine-46, and HPK1-PR blocked interleukin-2 (IL-2) induction in Jurkat T cells, suggesting that HPK1 signaling plays a critical role in IL-2 induction. Interestingly, HPK1 phosphorylated Crk and CrkL, mainly on serine and threonine residues in vitro. Taken together, our findings demonstrate the functional interaction of HPK1 with Crk and CrkL, reveal the downstream pathways of Crk- and CrkL-induced JNK activation, and highlight a potential role of HPK1 in T-cell activation.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Baylor College of Medicine, M929, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-4665. Fax: (713) 798-3700. E-mail: ttan{at}bcm.tmc.edu.

Molecular and Cellular Biology, February 1999, p. 1359-1368, Vol. 19, No. 2
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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