ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1

doi:10.1016/j.molcel.2022.04.034

ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1

2022-07-01

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Neilawattie Merna Timaul

DOI：10.1016/j.molcel.2022.04.034

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RAF protein kinases are effectors of the GTP-bound form of small guanosine triphosphatase RAS and func-tion by phosphorylating MEK. We showed here that the expression of ARAF activated RAS in a kinase-inde-pendent 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, ampli-fication 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.

Keywords:

CELL LUNG-CANCER

A-RAF

ONCOGENIC RAS

GROWTH-FACTOR

BRAF MUTANTS

INHIBITION

EXPRESSION

MUTATIONS

APOPTOSIS

FEEDBACK

ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1

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