Structural Biochemistry, Ras-ERK and PI3K-mTOR pathways

Ras-ERK and PI3K-mTOR pathways

Ras-extracellular signal-regulated kinase (Ras-ERK) is and phosphatidylinositol 3-kinase-mammalian target of rapamycin (PI3K-mTOR) signaling pathways are important for many major mechanisms in the cell.

Ras-ERK Pathway

ERK is a type of mitogen-activated protein kinase that plays a role as an effector for the Ras oncoprotein. The ERK-MAPK consists of Ras-GTPase, Raf kinase, MEK, and ERK. This pathway is activated by growth factors, polypeptide hormones, neurotransmitters, chemokines, and phorbol esters. When ERK is activated, it phosphorylates cytoplasmic signaling proteins and end-point effectors. Then, one of the cytoplasmic signaling proteins, p90 ribosomal S6 kinase, proceed to go phosphorylates other cytoplasmic targets and transcriptional regulators. Another pathway of ERK is nuclear targets, which are ternary complex factor transcription factors that functions to start the expression of immediate early genes. The end results of the pathways are to promote cell survival, cell division, and cell motility. Other Ras-ERK signaling pathways lead to the inhibition of cyclin-dependent kinase and trigger cell arrest.

PI3K-mTOR pathway
The PI3K-mTOR pathway is activated by growth factors, energy status, amino acid levels, and cellular stress. Growth factors turn on lipid kinase P13K by either recruiting the kinase protein directly or docking proteins insulin receptor substrate or GRB2-associated binder. Then, P13K phosphorylates photidylinositol 3,4,5 triphosphate (PIP3), which recruits protein kinase AKT to the plasma membrane. (AKT also phosphorylates many other factors involved survival, proliferation, and motility). Next, 3-phosphoinositide-dependent kinase 1 and mTOR complex are activated. The next step phosphorylates eukaryotic initiation factor 4E binding protein (4E-BP) and p70 ribosomal S6 kinase that start ribosome biogenesis and the translation of cell growth and proteins division. 4E-BP inhibition allows the assembly of cap-binding complex and translation initiation. Amino acids activate the pathway result in the activation of Rag GRPases. On the other hand, glucose deprivation and hypoxia causes AMP concentration to be increased that leads to AMP kinase to be turned on. This leads to the suppression of the pathway itself.

Other Information

The strength of the stimulus and the feedback loops affect the intensity and the duration of the pathway activation. In addition, some of the pathways initiation factors are the same. For example, insulin and insulin growth factors can activate the pathways, but it is a stronger P13K-mTORC1 pathway activator. Growth factors’ degree of strength depends on its quantity, the expression and cell surface localization of RTKs, and the co-expression of receptor family members and docking proteins. Positive and negative feedback loops also influence on the signal pathway dynamic. A positive loop is the GAB docking proteins that binds to RasGAP, Src homology 2-domain-containing protein tyrosine phosphatase, P13K, and PIP3. Consequently, GAB1 intensify P13K pathway. On the other hand, negative feedback loops suppress Ras-ERK and P13K-mTORC1 signaling pathways. An example is S6K phosphorylation of IRS and RICTOR that reduce AKT and mTORC1 activity.
Some research found clues that the two pathways can be integrated. One of the integrated pathways is cross-inhibition, where the two pathways regulate negatively regulate each other’s activity. An example is MEK inhibitors increase epidermal growth factor that starts AKT activation. However, this caused phosphorylation of GAB1, which suppresses the Ras-ERK pathways. Another is the pathway cross-inactivation. This integrated pathway is where Ras-ERK pathway causes the activation of P13K-mTORC1 pathway.

References: Mendoza, Michelle C., E. Emrah Er, and John Blenis. "The Ras-ERK and PI3K-mTOR Pathways: Cross-talk and Compensation." Trends in Biochemical Sciences (2011): 1-9. Print.

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