Blood: Genetic variation of N-RasG12D palmylation affects hematogenesis and hinders myelin conversion

Note: Palmylized modification, is an important form of lipid modification after protein translation, is an important mechanism to regulate the transport, stability, positioning and function of protein, at the same time, palmylation modification also participates in a variety of cell biological processes, and is closely related to the development of many diseasescancer-causing RAS mutations are a huge challenge for the development of effective drugsSequence variation within the High Frequency Variation Zone (HVR) of ras subtypes is the basis for differentiated post-translation modification and subcellular transport, which can lead to selective loopholesspecifically, inhibiting the palmylation/depalmylation cycle is an attractive strategy for treating NRAS mutant cancers, especially when normal tissue retention of K-Ras4b function allows physiological signal conductionthe role ofendogenous N-RasG12D palmylation in signal transduction, hematopoietic differentiation and myelin conversion is unclear, and solving these key problems will provide a theoretical basis for the development of new therapiesin order to evaluate palmylation/depalmylation cycle as a candidate drug target in an invivia-related model system, the researchers introduced the C181S mutation to the NrasG12D "knockin" allele under conditionsC181S second amino acid replacement curbs myelin conversion (associated with mislocation of non-palmylized N-Ras mutant proteins) and reduces Raf/MEK/ERK signaling and hematopoietic stem cell/progenitor cell variation through NrasG12DIn addition, the blood malignancies produced in NrasG12D/G12D, C181S composite hybrid mice always obtain a restorative mutation of cysteine 181in general, this study confirms that the palmylation cycle is a promising therapeutic target for NRAS mutant cancers