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.
Department of Systems Biology, MaCS-Magdeburg Centre for Systems Biology, Otto-von-Guericke-University Magdeburg, 39120 Magdeburg, Germany.
Anna
A
Dittrich
Tom
T
Quaiser
Christina
C
Khouri
Dieter
D
Görtz
Martin
M
Mönnigmann
Fred
F
Schaper
D015153:Blotting, Western; D002460:Cell Line; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism*; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
C508603:IL6R protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; D050822:Cytokine Receptor gp130; D053612:Janus Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11