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Review
. 2007 Aug;1773(8):1263-84.
doi: 10.1016/j.bbamcr.2006.10.001. Epub 2006 Oct 7.

Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance

James A McCubrey  1 , Linda S Steelman, William H Chappell, Stephen L Abrams, Ellis W T Wong, Fumin Chang, Brian Lehmann, David M Terrian, Michele Milella, Agostino Tafuri, Franca Stivala, Massimo Libra, Jorg Basecke, Camilla Evangelisti, Alberto M Martelli, Richard A Franklin
Affiliations
Review

Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance

James A McCubrey et al. Biochim Biophys Acta. 2007 Aug.

Abstract

Growth factors and mitogens use the Ras/Raf/MEK/ERK signaling cascade to transmit signals from their receptors to regulate gene expression and prevent apoptosis. Some components of these pathways are mutated or aberrantly expressed in human cancer (e.g., Ras, B-Raf). Mutations also occur at genes encoding upstream receptors (e.g., EGFR and Flt-3) and chimeric chromosomal translocations (e.g., BCR-ABL) which transmit their signals through these cascades. Even in the absence of obvious genetic mutations, this pathway has been reported to be activated in over 50% of acute myelogenous leukemia and acute lymphocytic leukemia and is also frequently activated in other cancer types (e.g., breast and prostate cancers). Importantly, this increased expression is associated with a poor prognosis. The Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways interact with each other to regulate growth and in some cases tumorigenesis. For example, in some cells, PTEN mutation may contribute to suppression of the Raf/MEK/ERK cascade due to the ability of activated Akt to phosphorylate and inactivate different Rafs. Although both of these pathways are commonly thought to have anti-apoptotic and drug resistance effects on cells, they display different cell lineage specific effects. For example, Raf/MEK/ERK is usually associated with proliferation and drug resistance of hematopoietic cells, while activation of the Raf/MEK/ERK cascade is suppressed in some prostate cancer cell lines which have mutations at PTEN and express high levels of activated Akt. Furthermore the Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways also interact with the p53 pathway. Some of these interactions can result in controlling the activity and subcellular localization of Bim, Bak, Bax, Puma and Noxa. Raf/MEK/ERK may promote cell cycle arrest in prostate cells and this may be regulated by p53 as restoration of wild-type p53 in p53 deficient prostate cancer cells results in their enhanced sensitivity to chemotherapeutic drugs and increased expression of Raf/MEK/ERK pathway. Thus in advanced prostate cancer, it may be advantageous to induce Raf/MEK/ERK expression to promote cell cycle arrest, while in hematopoietic cancers it may be beneficial to inhibit Raf/MEK/ERK induced proliferation and drug resistance. Thus the Raf/MEK/ERK pathway has different effects on growth, prevention of apoptosis, cell cycle arrest and induction of drug resistance in cells of various lineages which may be due to the presence of functional p53 and PTEN and the expression of lineage specific factors.

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Figures

Figure 1
Figure 1. Overview of Raf/MEK/ERK Pathway
The Raf/MEK/ERK pathway is regulated by Ras as well as various kinases, which serve to phosphorylate S/T and Y residues on Raf. Some of these phosphorylation events serve to enhance Raf activity (shown by a black P in a white circle) whereas others serve to inhibit Raf activity (shown by a white P in a black circle. Moreover there are phosphatases such as PP2A, which remove phosphates on certain regulatory residues. The downstream transcription factors regulated by this pathway are indicated in diamond shaped outlines.
Figure 2
Figure 2. MEK1/ERK Independent Effects of Raf-1
Many other non MEK1/ERK mediated functions of Raf-1 have been postulated. Some of the purported roles (e.g., cell cycle regulatory, anti-apoptotic effects on NF-κB activation) may be more likely than others (e.g., effects of Raf-1 on p53 transcription). BCR-ABL can activate Raf-1 activity and thus have anti-apoptotic and cell cycle effects. Raf can activate the Cdc25 phosphatase which results in CDK activation.
Figure 3
Figure 3. Overview of the PI3K/Akt Pathway
The PI3K/Akt pathway is activated either by the p85 PI3K regulatory subunit binding to an activated tyrosine residue on the activated growth factor receptor or via interaction with Ras. Both result in the membrane localization of PI3K. Some of the downstream effects of activation of PI3K pathway are shown. PIP2 is phosphorylated by PI3K to create PIP3 which promotes membrane localization of PDK1 through its PH domain. PDK1 then phosphorylates and activates Akt. Proteins activated by S/T phosphorylation induced by the PI3K/Akt pathway are indicated by a clear circle with a black P. Proteins inactivated by S/T phosphorylation induced by the PI3K/Akt pathway are shown in black circles with white P. Note that depending on the phosphorylation residue, some proteins can either be activated or inactivated by phosphorylation. Transcription factors are indicated by diamonds are similarly marked. Phosphatases are indicated in squares and those which inhibit activity are indicated in black rectangles (PTEN & SHIP) while the PP2A phosphatase which activates Raf is shown in a white rectangle. Arrows from phosphatases to the regulatory phosphates are indicated in open arrows.
Figure 4
Figure 4. Interactions between Raf/MEK/ERK and Apoptotic Pathways Resulting in Drug Resistance
Some of the potential downstream molecules activated by the Raf/MEK/ERK, PI3K/Akt and p53 and their effects on the induction of apoptosis are illustrated. The effects of Raf/MEK/ERK and PI3K/Akt on phosphorylation of apoptotic regulatory molecules which exert their effects on mitochondrial membrane potential and the prevention of apoptosis are indicated. Phosphorylation of these molecules by Raf/MEK/ERK and PI3K/Akt is associated with prevention of the caspase cascade and the induction of apoptosis. Activation of p53 by genotoxic stresses can result in the activation of PUMA and NOXA which can have pro-apoptotic effects. Activation of p53 can also result in transcription of hbEGF which would be predicted to have growth stimulatory effects. Drug resistance can result from Raf/MEK/ERK and PI3K/Akt pathways disrupting the balance between induction and prevention of apoptosis.
Figure 5
Figure 5. Interactions Between p53 and the Raf/MEK/ERK and PI3K/Akt Pathways
This figure summarizes some of the complex interactions between p53 and the Raf/MEK/ERK and PI3K/Akt pathways. These pathways are linked by complex interactions both directly and indirectly. These interactions can result in regulation of cell cycle progression as well as apoptosis. Dotted lines indicate indirect pathways.
Figure 6
Figure 6. Effects of PTEN Deletion on PI3K/Akt and Raf/MEK/ERK Activation in Prostate Cancer
PTEN deletion results in Akt activation. Akt activation can result in the phosphorylation and inactivation of Raf. This decrease in downstream MEK and ERK activation may lead to the loss of differentiation or senescence. Lack of Raf activation blocks p21Cip1 activation which may result in cell cycle progression. Akt activation can also result in the phosphorylation and inactivation of p21Cip1 and Foxo3a. Fox3a normally leads to the transcription of p27zlip1 and Puma which can act to inhibit cell cycle progression and promote apoptosis. Phosphorylated Foxo3a results in the suppression of p27kip1 and Puma transcription. Dotted lines indicate indirect pathways.
Figure 7
Figure 7. Sites of Action of Small Molecular Weight Signal Transduction Pathway Inhibitors
Potential sites of action of small molecular weight inhibitors are indicated. In some cases inhibitors will suppress growth, apoptotic and cell cycle regulatory pathways. This diagram serves to illustrate the concept that _targeting Raf/MEK/ERK and PI3K/Akt can have dramatic effects on many growth regulatory molecules. Proteins inactivated by S/T phosphorylation induced by the PI3K/Akt pathway are shown in black circles with white P in a black circle.
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