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A Bipolar Clamp Mechanism for Activation of Jak-Family Protein Tyrosine Kinases

Barua, D and Faeder, JR and Haugh, JM (2009) A Bipolar Clamp Mechanism for Activation of Jak-Family Protein Tyrosine Kinases. PLoS Computational Biology, 5 (4). ISSN 1553-734X

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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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Barua, D
Faeder, JRfaeder@pitt.eduFAEDER
Haugh, JM
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 April 2009
Date Type: Publication
Journal or Publication Title: PLoS Computational Biology
Volume: 5
Number: 4
DOI or Unique Handle: 10.1371/journal.pcbi.1000364
Schools and Programs: School of Medicine > Computational Biology
Refereed: Yes
ISSN: 1553-734X
PubMed Central ID: PMC2667146
PubMed ID: 19381268
Date Deposited: 25 Jul 2012 14:18
Last Modified: 22 Jun 2021 11:55


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