Trends in Biochemical Sciences
ReviewThe Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation
Section snippets
The Ras-ERK pathway
Extracellular signal-regulated kinase (ERK) is a mitogen-activated protein kinase (MAPK) that functions as the major effector of the Ras oncoprotein. MAPK pathways consist of an initial GTPase-regulated kinase (MAPKKK) that phosphorylates and activates an intermediate kinase (MAPKK) that, in turn, phosphorylates and activates an effector kinase (MAPK; Box 1). In the ERK-MAPK pathway, these components are the Ras GTPase and the protein kinases Raf, MEK and ERK (Figure 1a). Ras and the ERK-MAPK
Ras-ERK and PI3K-mTORC1 signaling dynamics
The intensity and duration of pathway activation are regulated by the strength of the stimulus and by feedback loops. The agonists involved in Ras-ERK activation overlap only partially with those that signal to PI3K-mTORC1. Phorbol 12-myristate 13-acetate (PMA) is generally a strong activator of the Ras-ERK pathway. By contrast, insulin and insulin growth factor 1 (IGF1) are weaker Ras-ERK activators, but strong PI3K-mTORC1 activators 9, 10. However, the degree of pathway activation by specific
Mechanisms of pathway integration
One of the first hints of Ras-ERK and PI3K-mTORC1 pathway integration arose during the early 1990s when our laboratory described both PI3K-dependent and -independent inputs into p70S6K activation [16]. In the intervening years, many mechanisms and modes of cross-talk have been uncovered. These include cross-inhibition, cross-activation, and pathway convergence on substrates (Box 2).
Whereas some of the kinases (Raf, MEK, and mTORC1) involved in these pathways have very narrow substrate
AGC kinase promiscuity
The Ras-ERK and PI3K-mTOR pathways additionally converge via AGC kinase promiscuity. The N-terminal kinase domain of RSKs and AKT, S6K, SGK, and PKC are all AGC kinases that share a similar architecture and a requirement for PDK1 phosphorylation of their activation loop [18]. The AKT–PDK1 interaction requires PDK1 interaction with PIP3 at the plasma membrane. By contrast, RSK, S6K, SGK, and PKC interact with PDK1 in the cytosol via their phosphorylated hydrophobic motifs 3, 18. When the
Therapeutic inhibition of Ras-ERK and PI3K-mTORC1
As major regulators of cell survival, proliferation, metabolism, and motility, the Ras-ERK and PI3K-mTORC1 pathways are commonly activated during oncogenesis. Owing to cross-activation and pathway convergence, the resulting activation of Ras-ERK and PI3K-mTOR signaling could theoretically facilitate the development of resistance to therapeutics targeting only one pathway. Indeed, concurrent KRAS/BRAF and PI3K/PTEN mutations reduce the cytostatic response of cancer cell lines to AKT and mTOR
Concluding remarks
The Ras-ERK and PI3K-mTORC1 pathways represent key mechanisms for cells to regulate cell survival, proliferation and motility. In addition to their independent signaling programs that provide compensatory mechanisms, the pathways cross-talk extensively and regulate each other both positively and negatively. Encouragingly, co-inhibition of both pathways has been successful in reducing tumor growth in xenograft cancer models and, importantly, in genetically engineered mouse models 97, 98. The
Acknowledgments
This work was funded by Susan G. Komen for the Cure (to M.C.M.) and the National Cancer Institute (NCI) grant R37CA46595 (to J.B.). J.B. is an Established Investigator of the LAM Foundation. We apologize for the fact there are many primary research papers and excellent reviews that we were unable to cite due to space limitations.
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