Abstract The protein-protein interaction in mitogen-activated protein kinase pathways play a very important role in cell signaling. The MAPK pathways has different functional cascades such as RAS-RAF-MEK and MEK-ERK-RSK. Different proteins present in pathways shuttle between cytoplasm and nucleus and perform different functions. The number of genetic variants reported in MAPK pathways are responsible for different cancers. Now the challenge is to categories the pathogenicity of variants. Some are simple polymorphs without any clinical significance. However, some are categories as pathogenic. Therefore, considering the role of MAPK in dissecting the signaling mechanism, we have performed multidisciplinary in-vitro, in-silico and biophysical approach to unravel the functions associated to RSKs. Ribosomal s6 Kinase1 (RSK) is a serine-threonine protein kinase comprises N-terminus kinase domain (NTKD) at N-terminus and a C-terminus kinase domain (CTKD) at C-terminus, and furthermore provides docking site for the different interacting proteins. RSKs are abnormally expressed proteins in different cancers such as pancreatic cancer, prostate cancer, breast cancer, acute myeloid leukemia. Pathogenicity of different mutations identified in RSK has been evaluated using in-silico prediction tools such as SIFFT, PolyPhen2, PMUT, PhD-SNP, and PROVEAN. Molecular dynamic simulations were performed to assess dynamics of the RSK mutants structures. To our observation, 10 out of 62 missense mutations located at RSK1-CTKD is deleterious. The molecular dynamic simulation analysis of mutants protein perturbs the overall conformational stability, flexibility, and integrity of RSK proteins. Reference: ACS Omega, doi.org/10.1021/acsomega.3c00722 Citation Format: Ashok K. Varma, Vaishnvee Chikhale, . Structural based assessment to evaluate pathogenicity of different variants identified in RAS-RSK pathways abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5440.
Varma et al. (Fri,) studied this question.