Open AccessBinding of SH2-B Family Members within a Potential Negative Regulatory Region Maintains JAK2 in an Active State
Author(s) -
Jason H. Kurzer,
Pipsa Saharinen,
Olli Silvennoinen,
Christin CarterSu
Publication year - 2006
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.00570-06
Subject(s) - sh2 domain , biology , janus kinase 2 , phosphotyrosine binding domain , tyrosine kinase , tyrosine , janus kinase , signal transducing adaptor protein , biochemistry , binding site , plasma protein binding , proto oncogene tyrosine protein kinase src , microbiology and biotechnology , signal transduction
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-Bβ and APS regulate the activity of JAK2. We show that like SH2-Bβ, 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-Bβ increase JAK2 activity independent of their N-terminal dimerization domains. SH2-Bβ-induced increases in JAK2 dimerization require only the SH2 domain and only one SH2-Bβ 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-Bβ 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.