Cell signalling pathways: energy, growth, survival and death
How cells sense energy and nutrients, decide to grow, recycle or die, and how drugs such as mTOR and BCL-2 inhibitors exploit these switches.
Besides receptors for hormones and transmitters, every cell has intrinsic pathways that sense nutrients and energy and decide between growth, self-recycling (autophagy) and programmed death (apoptosis). These pathways cross-talk with growth factor signalling, and several are direct drug targets in transplantation and cancer.
AMPK: the energy gauge
AMP-activated protein kinase is a three-part enzyme. When energy falls, AMP or ADP binds its regulatory subunit and the upstream kinase LKB1 phosphorylates it, switching it on. Glucose deprivation and calcium signals can also activate it. Active AMPK shuts down energy-consuming processes such as protein and lipid synthesis and turns on energy-producing ones. One of its key targets is mTORC1, which it inactivates.
mTOR: the growth switch
mTOR is a serine/threonine kinase that forms two complexes, mTORC1 and mTORC2. mTORC1 is activated by amino acids at the lysosome and by growth factors through the PI3K/AKT pathway and the small G protein RHEB; the tumour suppressors TSC1 and TSC2 restrain it. Active mTORC1 promotes protein synthesis and cell growth. Sirolimus and everolimus bind the intracellular protein FKBP-12, and the complex inhibits mTORC1 only. In cancer, this reduces cell proliferation, angiogenesis (lower HIF-1 and VEGF) and glucose uptake; in transplantation the same mechanism is used for immunosuppression.
Autophagy
Autophagy wraps damaged proteins, worn-out organelles and some microbes in double-membrane vesicles (autophagosomes) and delivers them to lysosomes for digestion. It recycles building blocks under stress or starvation. mTORC1 inhibits autophagy, AMPK promotes it, and more than thirty autophagy-related (ATG) genes run the steps. Autophagy appears protective in neurodegenerative diseases, while in cancer it can either suppress tumours or help established tumour cells survive.
Apoptosis
- Executors: caspases, proteases that are inactive in healthy cells and activated by apoptotic signals.
- Extrinsic (death receptor) pathway: TNF, Fas ligand or TRAIL bind their receptors, adaptors recruit and activate caspase 8, which activates caspase 3.
- Intrinsic (mitochondrial) pathway: DNA damage and p53 activate pro-apoptotic BCL-2 family proteins such as BAX; cytochrome c leaves mitochondria and, with Apaf-1, activates caspase 9 and then caspase 3.
- Brakes: anti-apoptotic BCL-2, BCL-XL and BCL-W; inhibitor of apoptosis proteins (IAPs).
- Drug example: venetoclax blocks BCL-2, freeing cancer cells to undergo apoptosis.
Integration of signals and pathway-targeted drugs
Real cells receive many signals at once, and there is ample cross-talk between pathways. In an arteriole wall, for example, constrictor signals such as angiotensin II and dilator signals such as nitric oxide act together, and vascular tone reflects their balance. Drugs exploit this: an ACE inhibitor such as enalapril removes one constrictor input, a nitrate adds a dilator one. The same G protein and arrestin signals can also be integrated differently in different cell types. In cancer, the PI3K/AKT/mTOR pathway is a frequent target; its constant activation can contribute to resistance to hormone therapy in breast cancer, an example of one pathway overriding the effect of a drug aimed at another.
Test yourself
Think of the answer, then tap the question to see it.
What activates AMPK, and what does it do to mTORC1?
Energy stress (more AMP or ADP relative to ATP) plus LKB1 phosphorylation activates it; AMPK then inactivates mTORC1.
How do sirolimus and everolimus inhibit mTOR?
They bind FKBP-12, and that complex inhibits mTORC1 (not mTORC2).
What distinguishes the intrinsic from the extrinsic pathway of apoptosis?
The extrinsic pathway starts at death receptors and caspase 8; the intrinsic one starts at mitochondria, controlled by BCL-2 proteins, with cytochrome c and caspase 9.
How does autophagy relate to mTORC1 and AMPK?
Active mTORC1 inhibits autophagy, while AMPK, switched on by energy stress, promotes it.
Example drugs
Connections
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: DailyMed - EVEROLIMUS tablet (DailyMed (U.S. National Library of Medicine), 2026); Venetoclax: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026).
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Representative model, for educational purposes only.