Constitutively active TrkB kinase signalling reduces actin filopodia dynamics and cell migration

Gupta, R.; Dittmeier, M.; Wohlleben, G.; Luzak, V.; Wegat, V.; Segebarth, D.; Bady, E.; Langlhofer, G.; Wachter, B.; Havlicek, S.; Lüningschrör, P.; Villmann, C.; Polat, B.; Monoranu, C. M.; Kuper, J.; Blum, R.

doi:10.1101/2020.09.11.292565

bioRxiv · 10.1101/2020.09.11.292565

Constitutively active TrkB kinase signalling reduces actin filopodia dynamics and cell migration

Gupta, R.·Dittmeier, M.·Wohlleben, G.·Luzak, V.·Wegat, V.·Segebarth, D.·Bady, E.·Langlhofer, G.·Wachter, B.·Havlicek, S.·Lüningschrör, P.·Villmann, C.·Polat, B.·Monoranu, C. M.·Kuper, J.·Blum, R.

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Abstract

Trk receptors and gene fusions of NTRK are targets in precision oncology. Classical Trk signalling concepts fail to explain ligand-independent signalling of intracellular TrkB or NTRK fusion proteins. Here, we show that abundance of the intracellular domain of TrkB is sufficient for ligand-independent autophosphorylation. This constitutive TrkB signalling reduced actin filopodia dynamics, could phosphorylate FAK, and changed cell morphology. Mutating Y705 in the kinase domain of TrkB alone specifically blocked these pathways. Engineered intracellular kinase domain proteins and a cancer-related intracellular NTRK2-fusion protein (SQSTM1-NTRK2) also underwent constitutive activation. In migrating glioblastoma-like U87MG cells, self-active TrkB kinase reduced cell migration. Moreover, we found evidences for constitutively active, intracellular TrkB in tissue of human grade IV glioblastoma. Structural modelling of the kinase domain let us postulate that release from cis-autoinhibition by abundance is sufficient for TrkB/FAK/Actin signalling via Y705. These constitutive signalling pathways could be fully blocked within minutes by clinically approved, anti-tumorigenic Trk inhibitors. In conclusion, our data provide an explanation and biological function for TrkB kinase domain signalling in the absence of a ligand.

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Gupta, R., Dittmeier, M., Wohlleben, G., Luzak, V., Wegat, V., Segebarth, D., Bady, E., Langlhofer, G., Wachter, B., Havlicek, S., Lüningschrör, P., Villmann, C., Polat, B., Monoranu, C. M., Kuper, J., Blum, R.. 2020-09-12. Constitutively active TrkB kinase signalling reduces actin filopodia dynamics and cell migration. https://doi.org/10.1101/2020.09.11.292565

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