ERK kinases in Cell Signaling: A Structural Study of Mechanisms and Cancer Therapeutics

Authors

• C Regev
• H Jang
• R Nussinov

Abstract

ERKs play essential roles in cell proliferation, differentiation, and survival. Within the MAPK signaling cascade, ERKs are the last and only components not restricted to the cytoplasm. Upon activation by MEK, ERKs translocate to the nucleus to regulate gene expression stimulating transcription factors. Dysregulation of ERK signaling has been implicated in cancers, making it one of the coveted therapeutic drug targets.
Regulation of ERK signaling is achieved by two main approaches: Indirect inhibitors targeting the upstream kinases, such as MEK (e.g., trametinib) or direct ERK inhibitors (e.g., ulixertinib). These orthosteric inhibitors have shown promise in the treatment of cancers with dysregulated ERK signaling, such as melanoma, colorectal and lung cancers.
Our aims are two-fold: discovering ERK’s activation mechanism, and its interaction network, both aiming at better understanding and drug discovery. Our molecular dynamics simulations sample the conformational ensembles within the inactive and active states, where highly homologous conformations are separated by low free energy barriers. We show that different ensembles of ERK conformations can be distinguished by the specificity of the phosphorylation code in the activation loop. Detailed structural studies focusing on the inhibition mechanisms can shed light on the reasons and conditions leading to kinase hyperactivity. We focus on ERK’s activation and deactivation mechanisms by investigating the structural differences of the intermediates and the stability in their monomeric and dimeric (binding MEK) states. We hope that our findings will contribute toward better anticancer drug targeting ERK regulation.

Scientific Focus Area: Computational Biology

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