Mechanical stretch induces phosphorylation of the hydrophobic motif site Thr(389) in p70(S6k) through a rapamycin-sensitive (RS) pathway that involves a unique PI3K-independent mechanism. Rapamycin is considered to be a highly specific inhibitor of the protein kinase mTOR; however, mTOR is also considered to be a PI3K-dependent signaling molecule. Thus, questions remain as to whether mTOR is the RS element that confers mechanically-induced signaling to p70(S6k)(389). In this study, rapamycin-resistant mutants of mTOR along with mechanical stretch were used to address this question. The results indicate that mTOR is the RS element and reveal that mTOR signaling can be activated through a PI3K-independent mechanism.
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http://dx.doi.org/10.1016/j.febslet.2007.08.045 | DOI Listing |
Nat Rev Cancer
November 2024
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Beyond their many well-established biological aberrations, solid tumours create an abnormal physical microenvironment that fuels cancer progression and confers treatment resistance. Mechanical forces impact tumours across a range of biological sizes and timescales, from rapid events at the molecular level involved in their sensing and transmission, to slower and larger-scale events, including clonal selection, epigenetic changes, cell invasion, metastasis and immune response. Owing to challenges with studying these dynamic stimuli in biological systems, the mechanistic understanding of the effects and pathways triggered by abnormally elevated mechanical forces remains elusive, despite clear correlations with cancer pathophysiology, aggressiveness and therapeutic resistance.
View Article and Find Full Text PDFPlant Cell Environ
April 2022
Hawkesbury Institute for the Environment, Western Sydney University, Richmond, New South Wales, Australia.
A single event of mechanical stimulation is perceived by mechanoreceptors that transduce rapid transient signalling to regulate gene expression. Prolonged mechanical stress for days to weeks culminates in cellular changes that strengthen the plant architecture leading to thigmomorphogenesis. The convergence of multiple signalling pathways regulates mechanically induced tolerance to numerous biotic and abiotic stresses.
View Article and Find Full Text PDFBioessays
May 2020
EMBL Australia, John Curtin School of Medical Research, The Australian National University, 131 Garran Rd, Acton 2602, Canberra, ACT, Australia.
The transcriptional co-activators YAP (or YAP1) and TAZ (or WWTR1) are frequently activated during the growth and progression of many solid tumors, including lung, colorectal, breast, pancreatic, and liver carcinomas as well as melanoma and glioma. YAP/TAZ bind to TEAD-family co-activators to drive cancer cell survival, proliferation, invasive migration, and metastasis. YAP/TAZ activation may also confer resistance to chemotherapy, radiotherapy, or immunotherapy.
View Article and Find Full Text PDFNature
February 2020
Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Shear stress on arteries produced by blood flow is important for vascular development and homeostasis but can also initiate atherosclerosis. Endothelial cells that line the vasculature use molecular mechanosensors to directly detect shear stress profiles that will ultimately lead to atheroprotective or atherogenic responses. Plexins are key cell-surface receptors of the semaphorin family of cell-guidance signalling proteins and can regulate cellular patterning by modulating the cytoskeleton and focal adhesion structures.
View Article and Find Full Text PDFNat Commun
December 2019
Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Goethestr. 33, 80336, Munich, Germany.
G-protein coupled receptors (GPCRs) are versatile cellular sensors for chemical stimuli, but also serve as mechanosensors involved in various (patho)physiological settings like vascular regulation, cardiac hypertrophy and preeclampsia. However, the molecular mechanisms underlying mechanically induced GPCR activation have remained elusive. Here we show that mechanosensitive histamine H receptors (HRs) are endothelial sensors of fluid shear stress and contribute to flow-induced vasodilation.
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