Paper Info
Title
A bipolar clamp mechanism for activation of Jak-family protein tyrosine kinases.
Abstract
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-B beta system. The modeling results suggest that, whereas Jak2-(SH2-B beta)(2)-Jak2 heterotetramers are scarcely expected to affect Jak2 phosphorylation, SH2-B beta 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.
Year
DOI
Venue
2009
10.1371/journal.pcbi.1000364
PLOS COMPUTATIONAL BIOLOGY
Keywords
Field
DocType
rule based,enzyme activation,sh2 domain,computer simulation,binding sites,adaptor protein,signal transduction,phosphorylation,protein domains,protein binding
SH2 domain,Proto-oncogene tyrosine-protein kinase Src,G protein-coupled receptor,Biology,Cell biology,Janus kinase,GRB2,Signal transduction,SH3 domain,Receptor tyrosine kinase
Journal
Volume
Issue
ISSN
5
4
1553-734X
Citations 
PageRank 
References 
7
0.61
0
Authors
3
Name
Order
Citations
PageRank
Dipak Barua1293.16
James R Faeder240931.02
Jason M Haugh391.54