Effect of SHP-2, SOCS3, and PP2 on IL-6 Signal Transduction in Hepatocytes

Signaling by interleukin-6 (IL-6) involves two pathways: Janus-associated kinases (JAK) & signal transducers and transcription factors (STAT 3) are activated in the first pathway while the second pathway involves the activation of mitogen-activated protein kinases (MAPK). While it is recognized that both pathways play a major role in IL-6 signal transduction, simultaneous signaling through both JAK/STAT and MAPK pathways has only been studied in few cases [1]. Additionally, the interaction between these pathways is not yet clearly understood.

In this work, a mathematical model has been developed that integrates signaling through both pathways. The presented model is used to analyze the effect of SHP-2 (domain containing tyrosine phosphatase 2), SOCS3 (suppressor of cytokine signaling 3), and PP2 (nuclear phosphatase) on signal transduction induced by IL-6. The results show that the presence of SOCS3 acts as a negative feedback on the activity of signaling in the JAK/STAT pathway. Additionally, the obtained results illustrate the interactions between SHP-2 and SOCS3 on the JAK/STAT and the MAPK pathway. It is shown that SHP-2 and SOCS3 do not just influence the pathway that they are mainly associated with, SHP-2 with MAPK and SOCS3 with JAK/STAT, but also have a profound effect on the other pathway due to interactions of the pathways. Several numerical experiments with various types of knockout cells have been performed to illustrate the effect of several of the key proteins.