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Molecular and Cellular Biology, September 2006, p. 6381-6394, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00570-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Binding of SH2-B Family Members within a Potential Negative Regulatory Region Maintains JAK2 in an Active State

Jason H. Kurzer,1 Pipsa Saharinen,2 Olli Silvennoinen,3 and Christin Carter-Su4*

Graduate Program in Cellular and Molecular Biology,1 Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0662,4 Molecular/Cancer Biology Laboratory, University of Helsinki, FIN-00014 Helsinki, Finland,2 Institute of Medical Technology, University of Tampere, and Department of Clinical Microbiology, Tampere University Hospital, FIN-33014 Tampere, Finland3

Received 31 March 2006/ Returned for modification 3 May 2006/ Accepted 26 June 2006

The tyrosine kinase Janus kinase 2 (JAK2) transduces signaling for the majority of known cytokine receptor family members and is constitutively activated in some cancers. Here we examine the mechanisms by which the adapter proteins SH2-Bß and APS regulate the activity of JAK2. We show that like SH2-Bß, APS binds JAK2 at multiple sites and that binding to phosphotyrosine 813 is essential for APS to increase active JAK2 and to be phosphorylated by JAK2. Binding of APS to a phosphotyrosine 813-independent site inhibits JAK2. Both APS and SH2-Bß increase JAK2 activity independent of their N-terminal dimerization domains. SH2-Bß-induced increases in JAK2 dimerization require only the SH2 domain and only one SH2-Bß to be bound to a JAK2 dimer. JAK2 mutations and truncations revealed that amino acids 809 to 811 in JAK2 are a critical component of a larger regulatory region within JAK2, most likely including amino acids within the JAK homology 1 (JH1) and JH2 domains and possibly the FERM domain. Together, our data suggest that SH2-Bß and APS do not activate JAK2 as a consequence of their own dimerization, recruitment of an activator of JAK2, or direct competition with a JAK2 inhibitor for binding to JAK2. Rather, they most likely induce or stabilize an active conformation of JAK2.

* Corresponding author. Mailing address: Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI 48109-0622. Phone: (734) 763-2561. Fax: (734) 647-9523. E-mail: cartersu{at}umich.edu.

Molecular and Cellular Biology, September 2006, p. 6381-6394, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00570-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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