Shawon, J. | bioRxiv Science

bioRxiv2025

Mechanism of ERK-mediated Rho Activation and Stress Fiber Assembly for Cell Migration

The growth factor-activated RAS/Extracellular Regulated Kinase (ERK) pathway is a fundamental regulatory pathway that induces cell migration. ERK supports protrusion of a leading edge and also activates the small GTPase Rho, which induces actin assembly into contractile stress fibers that pull the cell body forward. Yet, the mechanism behind ERKs induction of Rho in the cell body has remained elusive. We discover here that ERK controls Rho activity and contractile stress fibers by inhibiting Ezrin, a protein that physically links proximal actin filaments to the plasma membrane, but which also inhibits Rho by recruiting and activating ARHGAP18. ERK specifically reduces Ezrin activity in the cell body by phosphorylating the C-terminal tail of the Ezrin-activating kinase lymphocyte-oriented kinase (LOK). This phosphorylation inhibits LOKs activation of Ezrin, thereby releases Ezrins inhibition of Rho and stress fibers. The ERK-LOK-Ezrin-ARHGAP18-Rho signal provides key mechanistic insight into how ERK, activated during development, wound healing, and cancer, induces Rho activity and stress fibers for cell migration.

cell biology↗

bioRxiv2020

An extensive computational approach to inhibit MSP-1 of P.vivax elucidates further horizon in the establishment next generation therapeutics against malaria

Malaria represents a life-threatening disease caused by the obligate intra-erythrocytic protozoa of the Plasmodium genus, exerting a sinister global health burden and accounting for approximately 660,000 deaths annually. Additionally, 219 million new cases are reported each year, most of which result from the growing issue of artemisinin resistance shown by the Plasmodium parasite. Much of the research done for the purpose of development of therapeutics against malaria has traditionally been focused on Plasmodium falciparum, which is responsible for majority of the cases of mortality due to malaria, Plasmodium vivax is also known to contribute greatly towards the malaria relate morbidities particularly in vivax endemic areas. In this study, we have used two different computational approaches aimed at establishing newer concepts towards the development of advanced therapeutics against vivax malaria by targeting the surface antigen, merozoite surface protein-1 (MSP-1). In-silico approach involving computational siRNA designing against MSP-1 resulted in a total of four candidate siRNAs being rationally validated following corroboration with a plethora of algorithms. Additionally, molecular docking analysis unraveled a total of three anti-parasitic peptides. These peptides namely: AP02283, AP02285 and AP00101 were found to exhibit considerable binding affinity with MSP-1 of P.vivax, thus providing an apparent indication of their anti-malarial property and affirming their potency to be used as novel molecules for development of next generation anti-malarials. However, irrespective of the prospective magnitude of these in-silico findings, the results require extensive validation by further rigorous laboratory experiments involving both in-vitro and in-vivo approaches.

bioinformatics↗