PT  - JOURNAL ARTICLE
AU  - Einar B. Ólafsson
AU  - Arne L. ten Hoeve
AU  - Xiaoze Li Wang
AU  - Linda Westermark
AU  - Manuel Varas-Godoy
AU  - Antonio Barragan
TI  - Convergent Met and voltage-gated Ca<sup>2+</sup> channel signaling on Ras-Erk MAPK drives migratory activation of dendritic cells parasitized by <em>Toxoplasma gondii</em>
AID  - 10.1101/2020.01.08.898197
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.08.898197
4099  - http://biorxiv.org/content/early/2020/01/08/2020.01.08.898197.short
4100  - http://biorxiv.org/content/early/2020/01/08/2020.01.08.898197.full
AB  - Ras-Erk MAPK signaling controls many of the principal pathways involved in metazoan cell motility, drives metastasis of multiple cancer types and is targeted in chemotherapy. Yet, its putative roles in immune cell functions or in infections have remained elusive. Here, using primary dendritic cells (DCs) in an infection model with the protozoan Toxoplasma gondii, we show that two pathways activated by infection converge on Ras-Erk MAPK signaling to promote migration of parasitized DCs. We identify signaling through the receptor tyrosine kinase Met (also known as HGFR) as a driver of T. gondii-induced DC hypermotility. Further, we show that voltage-gated Ca2+channel (VGCC, subtype CaV1.3) signaling impacts the migratory activation of DCs via calmodulin-calmodulin kinase II. We report that VGCC and Met signaling converge on Ras GTPase to drive Erk1/2 phosphorylation and migratory activation of T. gondii-infected DCs. The data provide a molecular basis for the hypermigratory mesenchymal-to-amoeboid transition (MAT) of parasitized DCs. The emerging concept suggests that parasitized DCs acquire metastasis-like migratory properties to promote infection-related dissemination.