Abstract
Mitogenic and metabolic signalling are two cell pathways that control different aspects of cellular physiology including, growth, proliferation, metabolism, and transcription. Mitogenic signalling involves mitogens and growth factors to stimulate various receptor signalling pathways such as epidermal growth factor receptor (EGFR), while metabolic signalling involves proteins that sense changes in abundance of specific nutrients or metabolites such as amino acids and ATP. Here, I have uncovered that EGFR signalling is controlled by clathrin nanodomains at the plasma membrane, yet this requirement for clathrin does not reflect a role for receptor internalization in EGFR signalling. Specifically, I found that clathrin is required for activation of the key signaling intermediate Akt by EGFR upon EGF stimulation. Furthermore, I have also resolved a series of signals including Phospholipase C γ1 (PLCγ1) that may control EGF stimulated Akt activation by modulating the assembly of clathrin into plasma membrane nanodomains. These findings suggest that clathrin nanodomains at the plasma membrane are important for controlling EGFR signalling, thus impacting mitogenic signaling. A downstream signalling pathway controlled by Akt is the Glycogen synthase kinase 3 (GSK3) pathway. GSK3 phosphorylates and thereby regulates a wide range of protein substrates involved in diverse cellular functions. Some GSK3 substrates, such as c-Myc and Snail, are nuclear transcription factors, suggesting the possibility that GSK3 function is controlled through regulation of its nuclear localization. I found that perturbations in mTOR complex 1 (mTORC1) leads to partial redistribution of GSK3 from the cytosol to the nucleus and to a GSK3 dependent reduction of the levels of both c-Myc and Snail. In addition to conditional nuclear localization, GSK3 was also detected on several distinct endomembrane compartments, including lysosomes. Consistently, disruption of various aspects of the function and regulation late endosomes/lysosomes resulted in perturbation of GSK3 nucleocytoplasmic shuttling and activity. Furthermore, I found that DEPDC5, a subunit of the lysosomal amino-acid sensing GATOR1 complex, controls amino acid sensing mechanisms to regulate GSK3 nucleocytoplasmic shuttling. These findings uncover a new signalling axis that is controlled by specific aspects of both mitogenic and metabolic signalling, which may interface with the nucleus to reprogram transcriptional cellular networks for growth and proliferation. Understanding how mTORC1- GSK3 signalling impacts transcriptional networks may be an important target for different therapies and treatments against diverse forms of cancer.
Highlights
Hallmarks of cancerAs described in a seminal review article by Hanahan and Weinberg in 2000, cancers share six hallmarks or features that appear in cancer cells or within the tumor microenvironment (Hanahan and Weinberg, 2011; Hanahan and Weinberg, 2000)
One of the major mechanisms by which cancer cells exhibit an increase in uncontrolled growth, survival and proliferation, is by accumulating mutations in genes involved in environmental sensing mechanisms, one of which is in the proteins that bind to the small chemical hormone signals like epidermal growth factor (EGF), called epidermal growth factor receptor (EGFR)
Different signalling pathways and their impaired mechanisms contribute to cancer, many studies have examined EGFR as an important target due to disrupted function in cancer leading to pro-survival, uncontrolled growth, and resistance to many therapeutics
Summary
The human body is a complex system and each cell is constantly exposed to different environmental stimuli. Both glucose and amino acids are important molecules that supply the cell with energy and building blocks for the generation cellular biomolecules (Boroughs and DeBardinis, 2015). One of the major mechanisms by which cancer cells exhibit an increase in uncontrolled growth, survival and proliferation, is by accumulating mutations in (or otherwise exhibiting disruptions in the normal regulation of) genes involved in environmental sensing mechanisms, one of which is in the proteins that bind to the small chemical hormone signals like EGF, called EGFR
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