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Binding of SH2-B family members within a potential negative regulatory region maintains JAK2 in an active state.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2006 Sep; Vol. 26 (17), pp. 6381-94. - Publication Year :
- 2006
-
Abstract
- 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-Bbeta and APS regulate the activity of JAK2. We show that like SH2-Bbeta, 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-Bbeta increase JAK2 activity independent of their N-terminal dimerization domains. SH2-Bbeta-induced increases in JAK2 dimerization require only the SH2 domain and only one SH2-Bbeta 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-Bbeta 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.
- Subjects :
- Adaptor Proteins, Signal Transducing chemistry
Amino Acid Sequence
Animals
COS Cells
Carrier Proteins chemistry
Cells, Cultured
Chlorocebus aethiops
DNA, Complementary genetics
Dimerization
Enzyme Activation
Humans
Intracellular Signaling Peptides and Proteins
Janus Kinase 2
Mice
Molecular Sequence Data
Mutation genetics
Phosphotyrosine metabolism
Protein Binding
Protein-Tyrosine Kinases chemistry
Proto-Oncogene Proteins chemistry
Rats
Carrier Proteins metabolism
Protein-Tyrosine Kinases metabolism
Proto-Oncogene Proteins metabolism
Regulatory Sequences, Nucleic Acid genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0270-7306
- Volume :
- 26
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 16914724
- Full Text :
- https://doi.org/10.1128/MCB.00570-06