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

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.

P53 and PTEN expression contribute to the inhibition of EGFR downstream signaling pathway by cetuximab

“…This is consistent with data already reporting that P53 expression is decreased in PTENÀ/À cells 30 through the increase of MDM2 activation caused by overexpression of pAKT. In addition to its influence on PI3K activity and consequent inhibition of AKT signaling, P53 could further influence the cell response to P53, PTEN and cetuximab sensitivity S Bouali et al cetuximab through its potential consequence onto PDK1.…”

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

“…This ineffectiveness was probably due to Akt/Erk phosphorylation and activation during treatment as their level increased upon treatment. Similar indicators of resistance mechanisms have been observed both in cell lines and in biopsies from cancer patients treated with inhibitors of relevant pathways [80, 81]. …”

Encystation commitment inGiardia duodenalis: a long and winding road

“…These observations suggest the involvement of ERK1 in giardial mSREBP phosphorylation. Considering MAPK activation by the dual specificity MAPK kinases 1 and 2 (MAPKKs = MEK1/2; McCubrey et al, 2007), there is one giardial homolog of MEK1 (STE20 type) in the GiardiaDB (orf 22165) ( Table I). The sequences of human (393 aa long) and giardial (357 aalong) MEK1s show at most 39 % identity and 56 % homology (e.v.…”

“…human v-Raf-1, 648 aa-long) is atypical or truncated since the putative giardial homolog is shorter than the Raf-related G. gallus sequence displaying this domain (606 vs 1346 aa, respectively). In addition Raf-related sequences, including giardial Raf1-like, lack a Ras-binding domain (RBD) that allows Ras-mediated Raf translocation to cell membrane (McCubrey et al, 2007). To date one putative RBD has been described in the phosphatidylinositol-3-kinase-1 (PI3K1) sequence of this protist (Cox et al, 2006) and a Ras-like GTPase sequence was reported in the annotated GiardiaDB (orf 9718) suggesting that Ras-like is preferentially involved in the partially characterized PI3K signaling pathway of G. duodenalis (Cox et al, 2006;Morrison et al, 2002).…”

“…3). As an upstream activator of this pathway, Raf1 activity is positively regulated by protein kinase C and negatively regulated by PKA and protein phosphatase 2A (PP2A) (McCubrey et al, 2007). The catalytic subunit of giardial PKA (PKAc) retains the ability of protein expression at 2 h post-encystation induction without relocalizing from cytoskeletal structures to the cell membrane (Gibson et al, 2006).…”