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Figure 1. The regulatory mechanism of RAS/RAF/MEK/ERK signaling pathway. RAF and MEK exist as heterodimers in cytosol of quiescent cells (A). Upon Ras activation, these heterodimers are recruited to the plasma membrane where they form transient tetramers through side-to-side dimerization of RAF. Further, this side-to-side RAF dimerization activates RAF themselves and also loosens RAF/MEK heterodimers, which facilitate the MEK dimerization on the surface of RAF dimer. Subsequently, active RAF dimer phosphorylates MEK dimer docking on its surface or promotes intra-dimer MEK transphosphorylation. Thereafter, active MEK dimer docking on RAF dimer or released from RAF dimer phosphorylates and activates ERK. Since, unlike BRAF, CRAF and ARAF do not heterodimerize with MEK in inactive state, how MEK is delivered to CRAF and ARAF for activation remains unknown in current studies (B). EGF: Epidermal growth factor; RBD: RAS binding domain.