Optimización de las señales de ERK mediante transfosforilación entre diferentes proteínas scaffold: implicaciones en terapia antitumoral

The Ras/ERK pathway is noticeably linked to the development and progression of human malignancies. About 40% of human cancers harbor activating mutations in constituents of this pathway. One of the regulatory mechanisms is carried out by scaffold proteins, that modulate the intensity, amplitude and duration of ERK signals. For this reason, some scaffolds harbor a potential as antitumoral targets. In light of recent evidence unveiling direct interactions among different scaffold proteins species, we have considered the hypothesis that scaffold proteins must somehow interact with each other in order to regulate the flow of signals through the Ras/ERK pathway in a coordinated manner. This could be a possible explanation for the inefficacy of a novel small molecule KSR inhibitor. Indeed, we have shown that KSR1 and IQGAP1 mutants defective for binding MEK, can still associate to phosphorylated ERK. In this respect, we have found that KSR1 and IQGAP1 can directly interact among themselves, and in so doing they can “transphosphorylate” each other, enabling ERK phosphorylation in MEK-binding deficient mutants. Thus, associations among different scaffold proteins will add one further degree of regulation for an already tightly regulated cascade and could provide a novel means for manipulating ERK signals even with therapeutic purposes.