Activation and feedback regulation of the MAPK pathway
. The classical MAPK pathway is activated in human tumors by upstream receptor tyrosine kinases (RTK) or by mutations in RAS, BRAF, and MEK1.
RTKs activate RAS by recruiting adaptor proteins (e.g., GRB-2
) and exchange factors (e.g., SOS). RAS activation promotes the formation of RAF dimers, which activate MEK-ERK cascade
through phosphorylation. ERK pathway activity is regulated by negative feedback at multiple levels, including the transcriptional activation of DUSP proteins that negatively regulate the pathway. ERK also phosphorylates and thus regulates CRAF and MEK activity directly. ERK, or its immediate substrate
RSK, also phosphorylates SOS at several residues, inhibiting its activity and thus negatively regulating RAS activityTargeting ERK, an Achilles' Heel of the MAPK pathway, in cancer therapy
. Available from: https://www.researchgate.net/publication/323220502_Targeting_ERK_an_Achilles%27_Heel_of_the_MAPK_pathway_in_cancer_therapy