We are always talking about the role of growth factors or growth factor receptors  in the signaling pathway. For PI3K signaling pathway, we would think about over-expression of growth factors such as VEGF, or over-activated growth factor receptors including EGFR and HER2. It's true that over-activated EGFR, VEGFR or other growth factor receptors may lead to over-activated PI3K signaling pathway. Superfluous growth factors would also over-activated PI3K signaling pathway. But there are also other factors which can influence the PI3K signaling pathway. Today, we can talk about cAMP and ion channels, both of which can induce PI3K signaling pathway activation. And we just take PI3K signaling pathway as a pathway transforming different information from different sources.

Actually, cAMP itself is a famous second message in cells. And this is the structure of cAMP.
cAMP structure

cAMP structure

In this poster, I would link calcium ion channel, cAMP, and other RTKs together and gave a new and brief view of PI3K signaling pathway.
Ion channel is very important for cells and the channels can be regulated by some receptor tyrosine kinases. Calcium channel plays a key role in cell survive. One channel called canonical transient receptor potential 6 channels (TRPC6) can be activated and inactivated by some kinases so that calcium cation influx can be controlled. CaMKII and fyn, a src family kinase, can activate  transient receptor potential 6 channels. And PKC and PKG can inactivate  transient receptor potential 6 channels. Besides above, PKA also can influence  transient receptor potential 6 channels, but it's still not clear the details which PKA influence transient receptor potential 6 channels. What we know, so far, is that  PKA can phosphorylate  transient receptor potential 6 channels. In addition, Canonical transient receptor potential 6 channels (TRPC6) are Ca2+-permeable non-selective cation channels.

cAMP can induce calcium cation influx and cation whole-cell current in the cells which express  transient receptor potential 6 channels. Besides that, two different signaling pathways, PI3K signaling pathway and MAPK signaling pathway, cross-talk and participate calcium cation influx. Researchers used PI3K inhibitors (wortmannin and LY294002) and MEK inhibitors ( PD98059 and U0126) to prove the relationship between signaling pathways and calcium influx. Researchers found that ERK1/2 can directly phosphorylate the transient receptor potential 6 channels. And inhibition of MEK and PI3K lead to reducing calcium cation influx.

Researchers also test the role of other kinases in the whole-cell  current and they proved that PKA, EPAC and PNG showed no function on cAMP induced calcium influx. And cAMP did not alter the trans-location of  transient receptor potential 6 channels to the plasma membrane.

In conclusion, there is a complex signaling pathway regulating calcium influx which is cAMP-PI3K-Akt-MEK-ERK1/2-TRPC6. But there is still unclear that the cross-talk between PI3K signaling pathway and MAPK signaling pathway. The data cannot prove that PI3K and Akt are upstream kinases of MEK. And maybe we should consider more factors. Maybe we should compare the effect of PI3K and MEK dual inhibitor in other cells to this experiment. Maybe inhibition of PI3K and blocking MEK lead to the same inhibition of certain kinase.
LY294002, nvp-bez235, high through-out screening

Reference:
[1] Bing Shen et al. Cyclic AMP activates TRPC6 channels via PI3K-PKB-MEK-ERK1?2 signaling pathway. J Biol Chem. 2011 Jun 3;286(22):19439-45.
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