Wednesday, July 27, 2011
The extracelluar signal-regulated kinase (Erk) pathway
The Ras guanine nucleotide-binding proteins exist in an inactive GDP-bound form in unstimulated cells. Activation of receptor-associated PTKs results in the replacement of GDP by GTP, thus switching the Ras protein to an active conformation. GTP-bound Ras then activates the Raf protein kinase, triggering in turn the mitogen-activated protein kinase (Mek) and Erk. Erk-mediated phosphorylation of transcription factors including serum response factor (SRF) initiates cell-cycle entry via transcriptional upregulation of cell-cycle genes. Erk activation also blocks apoptosis, at least in part by phosphorylation of the pro-apoptotic protein Bim, resulting in Bim degradation within the proteasome.
Constitutive Erk activation in CLL cells
Malignant cells isolated from some CLL patients express constitutively activated Erk. Downregulation of active Erk precedes apoptosis induced by the Syk inhibitor R406. Treatment of CLL cells with flavopiridol or the vitamin D3 analog EB1089 decreases active Erk and induces apoptosis of CLL cells, suggesting that constitutive Erk activity confers apoptosis resistance. In vitro studies which investigate downstream consequences of Mek/Erk inhibition and its impact on apoptosis are needed to determine the role of this pathway in CLL. These studies may enhance attempts to target this pathway in a clinical setting.