Piezo1 activates noncanonical EGFR endocytosis and signaling

TY - JOUR

T1 - Piezo1 activates noncanonical EGFR endocytosis and signaling

AU - Pardo-Pastor, Carlos

AU - Rosenblatt, Jody

N1 - Funding Information: We thank C. Mulas, M. A. Valverde, and F. X. Real for critical reading of the manuscript; F. Fore and D. C. Bagley for help with mouse work; and E. Ortiz-Zapater, M. Rigau de Llobet, and the members of the Rosenblatt lab for their patience, technical input, and helpful discussions. This work was supported by a Human Frontiers Science Program Long-Term Fellowship LT000654/2019-L (C.P.-P.), a European Union’s Horizon 2020 research and innovation program Marie Skłodowska-Curie Fellowship 898067 (C.P.-P.), a Wellcome Trust Investigator Award 221908/Z/20/Z (J.R.), a Cancer Research UK DRCNPG-May21\100007 (J.R.), an Academy of Medical Sciences Professorship APR2\1007 (J.R.), and a King’s College London start-up grant (J.R.) Publisher Copyright: Copyright © 2023 The Authors, some rights reserved.

PY - 2023/9/29

Y1 - 2023/9/29

N2 - EGFR-ERK signaling controls cell cycle progression during development, homeostasis, and disease. While EGF ligand and mechanical inputs can activate EGFR-ERK signaling, the molecules linking mechanical force to this axis have remained mysterious. We previously found that stretch promotes mitosis via the stretch-activated ion channel Piezo1 and ERK signaling. Here, we show that Piezo1 provides the missing link between mechanical signals and EGFR-ERK activation. While both EGF- and Piezo1-dependent activation trigger clathrin-mediated EGFR endocytosis and ERK activation, EGF relies on canonical tyrosine autophosphorylation, whereas Piezo1 involves Src-p38 kinase-dependent serine phosphorylation. In addition, unlike EGF, ex vivo lung slices treated with Piezo1 agonist promoted cell cycle re-entry via nuclear ERK, AP-1 (FOS and JUN), and YAP accumulation, typical of regenerative and malignant signaling. Our results suggest that mechanical activation via Piezo1, Src, and p38 may be more relevant to controlling repair, regeneration, and cancer growth than tyrosine kinase signaling via canonical EGF signaling, suggesting an alternative therapeutic approach.

AB - EGFR-ERK signaling controls cell cycle progression during development, homeostasis, and disease. While EGF ligand and mechanical inputs can activate EGFR-ERK signaling, the molecules linking mechanical force to this axis have remained mysterious. We previously found that stretch promotes mitosis via the stretch-activated ion channel Piezo1 and ERK signaling. Here, we show that Piezo1 provides the missing link between mechanical signals and EGFR-ERK activation. While both EGF- and Piezo1-dependent activation trigger clathrin-mediated EGFR endocytosis and ERK activation, EGF relies on canonical tyrosine autophosphorylation, whereas Piezo1 involves Src-p38 kinase-dependent serine phosphorylation. In addition, unlike EGF, ex vivo lung slices treated with Piezo1 agonist promoted cell cycle re-entry via nuclear ERK, AP-1 (FOS and JUN), and YAP accumulation, typical of regenerative and malignant signaling. Our results suggest that mechanical activation via Piezo1, Src, and p38 may be more relevant to controlling repair, regeneration, and cancer growth than tyrosine kinase signaling via canonical EGF signaling, suggesting an alternative therapeutic approach.

UR - http://www.scopus.com/inward/record.url?scp=85172793967&partnerID=8YFLogxK

U2 - 10.1126/sciadv.adi1328

DO - 10.1126/sciadv.adi1328

M3 - Article

C2 - 37756411

AN - SCOPUS:85172793967

SN - 2375-2548

VL - 9

JO - Science Advances

JF - Science Advances

IS - 39

M1 - eadi1328

ER -