Tryptophan stress activates EGFR-RAS-signaling to MTORC1 and p38/MAPK to sustain translation and AHR-dependent autophagy


Limited supply and catabolism restrict the essential amino acid tryptophan (Trp) in tumors. How tumors sustain translation under Trp stress remains unclear. Unlike other amino acids, Trp stress activates the EGFR, which enhances macropinocytosis and RAS signaling to the MTORC1 and p38/MAPK kinases, sustaining translation. The AHR forms part of the Trp stress proteome and promotes autophagy to sustain Trp levels, and ceramide biosynthesis. Thus, Trp restriction elicits pro-translation signals enabling adaptation to nutrient stress, placing Trp into a unique position in the amino acid-mediated stress response. Our findings challenge the current perception that Trp restriction inhibits MTORC1 and the AHR and explain how both cancer drivers remain active. A glioblastoma patient subgroup with enhanced MTORC1 and AHR displays an autophagy signature, highlighting the clinical relevance of MTORC1-AHR crosstalk. Regions of high Trp or high ceramides are mutually exclusive, supporting that low Trp activates the EGFR-MTORC1-AHR axis in glioblastoma tissue.


DOI: 10.1101/2023.01.16.523931

Projects: MESI-STRAT

Publication type: Journal

Citation: biorxiv;2023.01.16.523931v1,[Preprint]

Date Published: 17th Jan 2023

Registered Mode: by DOI

Authors: Pauline Pfänder, Lucas Hensen, Patricia Razquin Navas, Marie Solvay, Mirja Tamara Prentzell, Ahmed Sadik, Alexander M. Heberle, Sophie Seifert, Leon Regin, Tobias Bausbacher, Anna-Sophia Egger, Madlen Hotze, Tobias Kipura, Bianca Berdel, Ivana Karabogdan, Luis F. Somarribas Patterson, Michele Reil, Deepak Sayeeram, Vera Peters, Jose Ramos Pittol, Ineke van ’t Land-Kuper, Teresa Börding, Saskia Trump, Alienke van Pijkeren, Yang Zhang, Fabricio Loayza-Puch, Alexander Kowar, Sönke Harder, Lorenz Waltl, André Gollowitzer, Tetsushi Kataura, Viktor I. Korolchuk, Shad A. Mohammed, Phillipp Sievers, Felix Sahm, Hartmut Schlüter, Andreas Koeberle, Carsten Hopf, Marcel Kwiatkowski, Christine Sers, Benoit J. Van den Eynde, Christiane A. Opitz, Kathrin Thedieck

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Pfänder, P., Hensen, L., Navas, P. R., Solvay, M., Prentzell, M. T., Sadik, A., Heberle, A. M., Seifert, S., Regin, L., Bausbacher, T., Egger, A.-S., Hotze, M., Kipura, T., Berdel, B., Karabogdan, I., Somarribas Patterson, L. F., Reil, M., Sayeeram, D., Peters, V., … Thedieck, K. (2023). Tryptophan stress activates EGFR-RAS-signaling to MTORC1 and p38/MAPK to sustain translation and AHR-dependent autophagy. In []. Cold Spring Harbor Laboratory.

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Created: 28th Nov 2023 at 18:55

Last updated: 28th Nov 2023 at 19:04

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