Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

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

[img]
Preview
PDF
Published Version
Available under License : See the attached license file.

Download (664kB) | Preview
[img] Plain Text (licence)
Available under License : See the attached license file.

Download (1kB)

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-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.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Barua, D
Faeder, JRfaeder@pitt.eduFAEDER
Haugh, JM
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorKannan, NatarajanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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: 02 Feb 2019 14:55
URI: http://d-scholarship.pitt.edu/id/eprint/13125

Metrics

Monthly Views for the past 3 years

Plum Analytics

Altmetric.com


Actions (login required)

View Item View Item