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Molecular and Cellular Biology, September 2001, p. 6102-6112, Vol. 21, No. 18
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.18.6102-6112.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Synergistic Regulation of Immunoreceptor Signaling by SLP-76-Related Adaptor Clnk and Serine/Threonine Protein Kinase HPK-1

Jie Yu,1 Catherine Riou,1 Dominique Davidson,1 Raman Minhas,1,2 Jeffrey D. Robson,1,2 Michael Julius,3,4 Ruediger Arnold,5 Friedemann Kiefer,5 and André Veillette1,2,6,7,*

Laboratory of Molecular Oncology, IRCM, Montréal, Québec, Canada H2W 1R71; Departments of Biochemistry,2 Medicine,6 and Microbiology and Immunology,7 McGill University, Montréal, Québec, Canada H3G 1Y6; Sunnybrook and Women's College Health Sciences Centre3 and the Departments of Immunology and Medical Biophysics,4 University of Toronto, Toronto, Ontario, Canada M4N 3M5; and the Max-Planck-Institute for Physiological and Clinical Research, W. G. Kerckhoff-Institute, D-61231 Bad Nauheim, Germany5

Received 20 March 2001/Returned for modification 26 April 2001/Accepted 18 June 2001

Recently, the identification of Clnk, a third member of the SLP-76 family of adaptors expressed exclusively in cytokine-stimulated hemopoietic cells, has been reported by us and by others. Like SLP-76 and Blnk, Clnk was shown to act as a positive regulator of immunoreceptor signaling. Interestingly, however, it did not detectably associate with known binding partners of SLP-76, including Vav, Nck, and GADS. In contrast, it became complexed in activated T cells and myeloid cells with an as yet unknown tyrosine-phosphorylated polypeptide of ~92 kDa (p92). In order to understand better the function of Clnk, we sought to identify the Clnk-associated p92. Using a yeast two-hybrid screen and cotransfection experiments with Cos-1 cells, evidence was adduced that p92 is HPK-1, a serine/threonine-specific protein kinase expressed in hemopoietic cells. Further studies showed that Clnk and HPK-1 were also associated in hemopoietic cells and that their interaction was augmented by immunoreceptor stimulation. A much weaker association was detected between HPK-1 and SLP-76. Transient transfections in Jurkat T cells revealed that Clnk and HPK-1 cooperated to increase immunoreceptor-mediated activation of the interleukin 2 (IL-2) promoter. Moreover, the ability of Clnk to stimulate IL-2 promoter activity could be blocked by expression of a kinase-defective version of HPK-1. Lastly we found that in spite of the differential ability of Clnk and SLP-76 to bind cellular proteins, Clnk was apt at rescuing immunoreceptor signaling in a Jurkat T-cell variant lacking SLP-76. Taken together, these results show that Clnk physically and functionally interacts with HPK-1 in hemopoietic cells. Moreover, they suggest that Clnk is capable of functionally substituting for SLP-76 in immunoreceptor signaling, albeit by using a distinct set of intracellular effectors.

* Corresponding author. Mailing address: Laboratory of Molecular Oncology, IRCM, 110 Pine Ave. West, Montréal, Québec, Canada H2W 1R7. Phone: (514) 987-5561. Fax: (514) 987-5562. E-mail: veillea{at}ircm.qc.ca.

Molecular and Cellular Biology, September 2001, p. 6102-6112, Vol. 21, No. 18
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.18.6102-6112.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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