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-Bb system. The modeling results suggest that, whereas Jak2-(SH2-Bb)2-Jak2 heterotetramers are scarcely expected to affect Jak2 phosphorylation, SH2-Bb 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.
D. Barua et al., "A Bipolar Clamp Mechanism for Activation of Jak-Family Protein Tyrosine Kinases," PLoS Computational Biology, vol. 5, no. 4, PLoS ONE, Apr 2009.
The definitive version is available at https://doi.org/10.1371/journal.pcbi.1000364
Chemical and Biochemical Engineering
Keywords and Phrases
Growth Hormone Receptor; Janus Kinase; Protein Tyrosine Phosphatase SHP; Janus Kinase; Sh2bpsm1 Protein, Mouse; Signal Transducing Adaptor Protein, Article; Clamp; Combinatorial Chemistry; Dimerization; Kinetics; Molecule; Phosphorylation; Protein Domain; Protein Interaction; Protein Stability; Protein Structure; Regulatory Mechanism; Signal Transduction; Transactivation; Binding Site; Biological Model; Chemical Model; Chemistry; Computer Simulation; Enzyme Activation; Metabolism; Physiology; Protein Binding; Signal Transduction, Adaptor Proteins, Signal Transducing; Binding Sites; Computer Simulation; Enzyme Activation; Janus Kinases; Models, Biological; Models, Chemical; Phosphorylation; Protein Binding; Signal Transduction
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01 Apr 2009