AI Article Synopsis
- RAF protein kinases play a role in RAS activation by phosphorylating MEK, but ARAF can activate RAS independently of its kinase function.
- ARAF binds to RAS, preventing the GTPase-activating protein NF1 from inhibiting RAS, leading to increased levels of active RAS-GTP.
- In lung cancers with EGFR mutations, ARAF amplification contributes to resistance against EGFR inhibitors, which can be addressed by using SHP2 inhibitors to improve the effectiveness of these therapies.
Article Abstract
RAF protein kinases are effectors of the GTP-bound form of small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that the expression of ARAF activated RAS in a kinase-independent manner. Binding of ARAF to RAS displaced the GTPase-activating protein NF1 and antagonized NF1-mediated inhibition of RAS. This reduced ERK-dependent inhibition of RAS and increased RAS-GTP. By this mechanism, ARAF regulated the duration and consequences of RTK-induced RAS activation and supported the RAS output of RTK-dependent tumor cells. In human lung cancers with EGFR mutation, amplification of ARAF was associated with acquired resistance to EGFR inhibitors, which was overcome by combining EGFR inhibitors with an inhibitor of the protein tyrosine phosphatase SHP2 to enhance inhibition of nucleotide exchange and RAS activation.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9271631 | PMC |
| http://dx.doi.org/10.1016/j.molcel.2022.04.034 | DOI Listing |
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