A bipolar clamp mechanism for activation of Jak-family protein tyrosine kinases

Most cell surface receptors for growth factors and cytokines dimerize in order to mediate signal transduction. For many such receptors, the Janus kinase (Jak) family of non-receptor protein tyrosine kinases are recruited in pairs and juxtaposed by dimerized receptor complexes in order to activate on...

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Bibliographic Details
Published in:PLoS computational biology 2009-04, Vol.5 (4), p.e1000364-e1000364
Main Authors: Barua, Dipak, Faeder, James R, Haugh, Jason M
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - chemistry
Adaptor Proteins, Signal Transducing - metabolism
Binding Sites
Biophysics/Cell Signaling and Trafficking Structures
Cell Biology/Cell Signaling
Cell receptors
Cellular signal transduction
Computational Biology/Signaling Networks
Computer Simulation
Enzyme Activation
Enzymes
Growth hormones
Janus Kinases - chemistry
Janus Kinases - metabolism
Kinases
Models, Biological
Models, Chemical
Phosphorylation
Physiological aspects
Protein Binding
Protein kinases
Proteins
Signal transduction
Signal Transduction - physiology
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Summary:Most cell surface receptors for growth factors and cytokines dimerize in order to mediate signal transduction. For many such receptors, the Janus kinase (Jak) family of non-receptor protein tyrosine kinases are recruited in pairs and juxtaposed by dimerized receptor complexes in order to activate one another by trans-phosphorylation. An alternative mechanism for Jak trans-phosphorylation has been proposed in which the phosphorylated kinase interacts with the Src homology 2 (SH2) domain of SH2-B, a unique adaptor protein with the capacity to homo-dimerize. Building on a rule-based kinetic modeling approach that considers the concerted nature and combinatorial complexity of modular protein domain interactions, we examine these mechanisms in detail, focusing on the growth hormone (GH) receptor/Jak2/SH2-Bbeta system. The modeling results suggest that, whereas Jak2-(SH2-Bbeta)(2)-Jak2 heterotetramers are scarcely expected to affect Jak2 phosphorylation, SH2-Bbeta and dimerized receptors synergistically promote Jak2 trans-activation in the context of intracellular signaling. Analysis of the results revealed a unique mechanism whereby SH2-B and receptor dimers constitute a bipolar 'clamp' that stabilizes the active configuration of two Jak2 molecules in the same macro-complex.
ISSN:1553-7358
1553-734X
1553-7358
DOI:10.1371/journal.pcbi.1000364