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Borisov et al. (2009), Systems-level interactions between insulin-EGF networks amplify mitogenic signaling.

March 2010, model of the month by Christine Seeliger
Original model: BIOMD0000000223

Epidermal growth factor (EGF) as well as Insulin act on their target cells through binding to their respective receptors. The EGF receptor (EGFR) as well as the Insulin receptor (IR) belong to the family of receptor tyrosine kinases. Upon ligand binding, these receptors form dimers and phosphorylate their cytoplasmic tails. EGFR activates mitogenic signaling that results in cell proliferation, differentiation, and survival. In many cancers, EGFR seems to be overexpressed. Insulin on the other hand is most widely known for its role in Diabetes where the glucose metabolism is impaired due to a decrease in IR numbers. However, both receptors activate overlapping signaling pathways (cp. Insulin and EGF pathways in KEGG Pathway)

Flow chart of signal propagation through the EGFR and IR networks

Figure 1: Flow chart of signal propagation through the EGFR and IR networks. Figure taken from [1]

Mechanism of Insulin-EGF integration

Figure 2: Mechanism of Insulin-EGF integration. Figure taken from [1]

The signal propagation through EGFR and IR is shown in figure 1 (figure taken from [1]). The mitogenic signal is propagated from both receptors through the Ras/Erk pathway. First, the small G-Protein Ras is activated. Ras then phosphorylates the first serine/threonine kinase of the MAPK/Erk pathway, the MAP kinase Raf (detailed reviews on MAPK signaling can be found in [2] and [3]). Both receptors are also able to activate the PI3K/Akt pathway. However, the details of the activation of those cascades differ between the two receptors. IR recruits PI3K either directly or via IRS and activates the MAPK pathway by IRS mediated recruitment of Grb2-SOS. EGFR recruits Grb2-SOS either directly or via the adaptor Shc. PI3K is activated rather indirectly. The activation of PI3K and subsequent production of PIP3 recruits the docking proteins GAB1 and IRS to the membrane. This releases the intrinsic PI3K inhibition. Both also recruit Grb2-SOS thereby influencing the Ras/Erk pathway. SHP2, a phosphatase, is also recruited via GAB1 and IRS. Usually, SHP2 is a negative regulator of PI3K signaling but it has a positive influence on Erk activity because it dephosphorylates RasGAP binding sites thereby inhibiting its negative regulation of Ras.

In Borisov et al., ([1],BIOMD0000000223) a new deterministic model of integrated EGF and Insulin signaling cascades is presented. This model is based on previously published EGF signaling models (BIOMD0000000019, BIOMD0000000048) that were extended to include the IR pathway and to account for the interconnections between both pathways (see figure 1). The model was simplified where appropriate by condensing sequential signaling steps and by modeling multiple phosphorylation sites as one. In addition, simulation results and predictions where validated against experimental results obtained in HEK293 cells. The model should help to elucidate the systems-level interactions and identify important crosstalk points and help explaining experimentally observed signaling patterns. The three key mechanisms of EGF and Insulin signaling integration are summarized in figure 2.

Figure 3

Figure 3: Dynamics of EGF or Insulin induced Ras and Erk activation. Figure taken from [1]

Figure 4

Figure 4: Insulin amplifies EGF-induced Ras/MAPK pathway action at low EGF doses. Figure taken from [1]

First, Insulin is a strong activator of the PI3K signaling pathway whereas it fails to promote sufficient activation of the Ras/Erk pathway (figure 3A and 3B) on its own. Due to PI3K activation and the generation of PIP3, several adapter molecules especially GAB1 and IRS are recruited to the membrane. The IR kinase is able to phosphorylate PIP3-IRS, but not PIP3-GAB1 and therefore fails to activate the Ras/Erk cascade (figure 2A). On the other hand, EGF mediates the phosphorylation of PIP3-GAB1. Phospho-GAB1 activates the Ras/Erk pathway very efficiently by recruiting Grb2-SOS as well as SHP2. The positive effect of SHP2 itself stems from its dephosphorylation of RasGAP binding sites. It thereby inhibits a negative regulator of Ras (figure 2B). In addition, Src activation by EGFR enhances GAB1 and Raf activation. Synergistic effects (figure 4A) between EGFR and IR signaling occur mainly on the level of the PIP3-GAB1 positive feedback loop (figure 2C). GAB1 is recruited to the membrane due to IR activation and subsequently gets phosphorylated by EGFR. Different experimental results underline, that GAB1 is one of the major crosstalk points. Wortmannin, an inhibitor of PI3K, supresses the synergistic effect of Insulin on EGF signaling (figure 4A). This goes along with a reduction in GAB1 phosphorylation levels and thereby reduced recruitment of Grb2, SHP2 and PI3K into signaling complexes. Insulin EGF crosstalk also seems to render the activation of ERK less prone to depletion of GAB1 (figure 5) since Erk can still be activated via the PIP3-IRS route. Another group of crosstalk events takes place downstream of Ras by increasing Raf activity. This is due to EGF mediated SFK activation. An additional inhibiting effect of AKT on Raf seems to be neglectible in experiments and simulations.

Models, like the presented, aid the understanding of complex signaling networks in a cell and the understanding of experimental results. Studies on single pathways are useful, but to get an idea of the overall cellular response it is important to consider pathway crosstalk. The EGF pathway is very often involved in cancer development and an understanding of how mitogenic signaling is modified by other stimuli might lead to new directions in the treatment of cancer diseases.

Figure 5

Figure 5: Effects of GAB1 depletion on ERK activation induced by EGF, insulin or their combination. Figure taken from [1]

Bibliographic References

  1. Borisov N, Aksamitiene E, Kiyatkin A, Legewie S, Berkhout J, Maiwald T, Kaimachnikov NP, Timmer J, Hoek JB, Kholodenko BN. Systems-level interactions between insulin-EGF networks amplify mitogenic signaling. Mol. Syst. Biol. 5: 256, 2009. [CiteXplore]
  2. Kolch W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol., 6(11):827-37, 2005. [CiteXplore]
  3. McKay MM, Morrison DK. Integrating signals from RTKs to ERK/MAPK. Oncogene, 26(22):3113-21, 2007 [CiteXplore]
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