Model-driven experimental analysis of the function of SHP-2 in IL-6-induced Jak/STAT signaling.
Summary of "Model-driven experimental analysis of the function of SHP-2 in IL-6-induced Jak/STAT signaling."
Misregulated interleukin-6 (IL-6)-induced Jak/STAT signaling contributes to many diseases. Under non-pathological conditions Jak/STAT signaling is tightly regulated by a complex network of regulators. One of these regulators is the protein tyrosine phosphatase SH2-containing phosphatase 2 (SHP2). Although SHP2 is known to be a negative regulator of IL-6-induced Jak/STAT signaling, its exact molecular function is not entirely understood. To elucidate the function of SHP2 in IL-6 signaling we followed a systems biology approach, in which modeling, stepwise model refinement, and experimental analysis are closely linked. We come up with an identifiable model of early Jak/STAT signaling that describes the data and proves to be predictive. The model-based analysis implies that (1) the stepwise association of IL-6 with gp80 and gp130 and (2) STAT3 dimerization at the receptor are essential for the dynamics of early pathway activation, and (3) phosphorylation of SHP2 is nonlinear. Furthermore, the modeling results indicate that SHP2 does not act as a feedback inhibitor in an early phase of IL-6-induced Jak/STAT signaling. However, experimental data reveal that SHP2 exhibits a basal repressory function.
Affiliation
Department of Systems Biology, MaCS-Magdeburg Centre for Systems Biology, Otto-von-Guericke-University Magdeburg, 39120 Magdeburg, Germany. fred.schaper@ovgu.de.
Journal Details
This article was published in the following journal.
Name: Molecular bioSystems
ISSN: 1742-2051
Pages: 2119-34
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22711165
- DOI: http://dx.doi.org/10.1039/c2mb05488d
Medical and Biotech [MESH] Definitions
Janus Kinases
A family of intracellular tyrosine kinases that participate in the signaling cascade of cytokines by associating with specific CYTOKINE RECEPTORS. They act upon STAT TRANSCRIPTION FACTORS in signaling pathway referred to as the JAK/STAT pathway. The name Janus kinase refers to the fact the proteins have two phosphate-transferring domains.
Stat Transcription Factors
A family of transcription factors containing SH2 DOMAINS that are involved in CYTOKINE-mediated SIGNAL TRANSDUCTION. STAT transcription factors are recruited to the cytoplasmic region of CELL SURFACE RECEPTORS and are activated via PHOSPHORYLATION. Once activated they dimerize and translocate into the CELL NUCLEUS where they influence GENE expression. They play a role in regulating CELL GROWTH PROCESSES and CELL DIFFERENTIATION. STAT transcription factors are inhibited by SUPPRESSOR OF CYTOKINE SIGNALING PROTEINS and PROTEIN INHIBITORS OF ACTIVATED STAT.
Sarcoma, Experimental
Experimentally induced neoplasms of CONNECTIVE TISSUE in animals to provide a model for studying human SARCOMA.
Models, Statistical
Statistical formulations or analyses which, when applied to data and found to fit the data, are then used to verify the assumptions and parameters used in the analysis. Examples of statistical models are the linear model, binomial model, polynomial model, two-parameter model, etc.
Melanoma, Experimental
Experimentally induced tumor that produces MELANIN in animals to provide a model for studying human MELANOMA.
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