| Abstract | Here, we report a novel hybrid mathematical modeling strategy to systematically unravel hepatocyte growth factor (HGF) stimulated phosphoinosi-tide-3-kinase (PI3K) and mitogen activated protein kinase ( MAPK ) signaling, which critically contribute to liver regeneration. |
| Author Summary | Specifically, we analyze the interconnections within and between PI3K and MAPK signaling pathways involved in hepatocytes proliferation. |
| Introduction | Upon binding to its receptor Met, HGF activates the phosphoinositide-(PI)-3-kinase (PI3K) and the mitogen activated protein kinase ( MAPK ) signaling pathways. |
| Introduction | Conditional knock-in mice that harbor an inactivating mutation of Met show reduced activation of PI3K signaling and complete abrogation of the activation of the MAPK pathway in response to partial hepatectomy [2]. |
| Introduction | While PI3K can be activated by direct binding to the receptor, MAPK signaling requires the activation of SOS and Ras that in turn activates Raf initiating the MAPK signaling cascade. |
| Supporting Information | Inferred 8 gene MAPK networks on HRV infection data. |
| Supporting Information | Best networks of the 8 top scoring siRNAs from the MAPK pathway for HRV infection for the different compared methods are displayed. |
| Supporting Information | Performance of MAPK network inference. |
| Introduction | The well-studied mitogen-activated kinase ( MAPK ), and in particular extracellular signal-reg-ulated kinase (ERK) pathways, play important roles in signal transduction in the immediate-early response as well as many other cellular responses [1]. |
| Kinetics and chromatin features underlying IEG induction | Targets of the MAPK cascade in Fig 2C included the transcription factors ETV3 and KLF4 [30] as well as IEGs [UN and PCS [26]. |
| The early peak signature is enriched for lEGs and signalling pathways | RTKs can stimulate cells through either the MAPK pathway, the AKT/PI3K pathway, or a combination of the two [25]. |
| The early peak signature is enriched for lEGs and signalling pathways | The promoters of IEGs [UN and F08 contain a number of elements that are targets for MAPK signalling [26]. |
| The early peak signature is enriched for lEGs and signalling pathways | Pathway analysis indicates that kinetic signatures identify the transcription of genes linked to the RTK, AKT, MAPK and NF-KB pathways. |