PMID- 22711165
OWN - NLM
STAT- MEDLINE
DCOM- 20121031
LR  - 20120704
IS  - 1742-2051 (Electronic)
IS  - 1742-2051 (Linking)
VI  - 8
IP  - 8
DP  - 2012 Aug
TI  - Model-driven experimental analysis of the function of SHP-2 in IL-6-induced 
      Jak/STAT signaling.
PG  - 2119-34
LID - 10.1039/c2mb05488d [doi]
AB  - 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.
FAU - Dittrich, Anna
AU  - Dittrich A
AD  - Department of Systems Biology, MaCS-Magdeburg Centre for Systems Biology, 
      Otto-von-Guericke-University Magdeburg, 39120 Magdeburg, Germany.
FAU - Quaiser, Tom
AU  - Quaiser T
FAU - Khouri, Christina
AU  - Khouri C
FAU - Gortz, Dieter
AU  - Gortz D
FAU - Monnigmann, Martin
AU  - Monnigmann M
FAU - Schaper, Fred
AU  - Schaper F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120619
PL  - England
TA  - Mol Biosyst
JT  - Molecular bioSystems
JID - 101251620
RN  - 0 (IL6R protein, human)
RN  - 0 (Interleukin-6)
RN  - 0 (Receptors, Interleukin-6)
RN  - 0 (STAT Transcription Factors)
RN  - 0 (STAT3 Transcription Factor)
RN  - 133483-10-0 (Cytokine Receptor gp130)
RN  - EC 2.7.10.2 (Janus Kinases)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
SB  - IM
MH  - Blotting, Western
MH  - Cell Line
MH  - Cytokine Receptor gp130/metabolism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Flow Cytometry
MH  - Humans
MH  - Interleukin-6/*pharmacology
MH  - Janus Kinases/*metabolism
MH  - Phosphorylation
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11/*metabolism
MH  - Receptors, Interleukin-6/metabolism
MH  - STAT Transcription Factors/*metabolism
MH  - STAT3 Transcription Factor/metabolism
MH  - Signal Transduction/drug effects
EDAT- 2012/06/20 06:00
MHDA- 2012/11/01 06:00
CRDT- 2012/06/20 06:00
PHST- 2012/06/20 06:00 [entrez]
PHST- 2012/06/20 06:00 [pubmed]
PHST- 2012/11/01 06:00 [medline]
AID - 10.1039/c2mb05488d [doi]
PST - ppublish
SO  - Mol Biosyst. 2012 Aug;8(8):2119-34. doi: 10.1039/c2mb05488d. Epub 2012 Jun 19.