1992 Nobel Prize in Physiology or Medicine
Reason for Award
for the discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism
Laureates
Switzerland, 
United States of America
United States of America
Explanation
Our body cells use many proteins to keep us alive. Drs. Fischer and Krebs discovered that putting a tiny tag called a phosphate on a protein, and later removing it, works like an on-off switch. When the phosphate is on, the protein is active; when it is removed, the protein rests. Thanks to this simple switch, cells control things such as making energy or moving muscles at just the right time. Knowing this switch helps scientists understand illnesses and invent new medicines.
Related Keywords
protein phosphorylation
A chemical reaction in which a kinase transfers the γ-phosphate of ATP to serine, threonine or tyrosine side chains of proteins. The modification alters charge and conformation, profoundly changing enzymatic activity or binding capacity. Because phosphatases can rapidly remove the group, the process acts as a reversible molecular switch. It enables both signal amplification and tight temporal control, integrating metabolism, cell cycle and immune responses. Aberrant phosphorylation often underlies cancer and neurodegenerative diseases.
protein kinase
Enzymes that catalyze phosphorylation; more than 500 are encoded in the human genome. A conserved catalytic domain contains an ATP-binding pocket and an activation loop whose conformation dictates activity, while regulatory subunits or lipid-binding modules modulate specificity. Sub-families include receptor tyrosine kinases, serine/threonine kinases and histidine kinases of two-component systems. Kinase cascades amplify signals in discrete steps, turning small stimuli into large outputs. Numerous small-molecule inhibitors have been developed, making kinases a cornerstone of targeted cancer therapy.
phosphatase
Enzymes that remove phosphate groups, keeping cellular phosphorylation in balance. They are broadly divided into serine/threonine phosphatases such as PP1 and PP2A and tyrosine phosphatases such as PTP1B. Many use metal ions or a nucleophilic cysteine in their catalytic mechanism. Diverse localization signals and regulatory subunits confer substrate specificity. Hyper- or hypoactivity is linked to cytokine resistance and loss of tumor suppressor function, prompting drug development of both inhibitors and activators.
ATP
Adenosine triphosphate serves as the cell’s universal energy currency and provides the phosphate donor in kinase reactions. Transfer of the γ-phosphate converts ATP to ADP, releasing free energy. Cells regenerate ATP via glycolysis and oxidative phosphorylation at extremely high turnover rates. Intracellular ATP levels act as sensors of energy status and regulate metabolic flux. Because kinase velocity is ATP-dependent, cellular energy state is tightly interwoven with signaling pathways.
signal transduction
A collective term for processes that convert external stimuli into intracellular chemical changes, culminating in responses such as transcriptional control or metabolic adjustment. Phosphorylation is the most ubiquitous switch, conveying information from activated receptors to the nucleus. Multi-tiered kinase cascades filter noise and create quasi-digital on/off outputs. Negative feedback and pathway crosstalk provide both robustness and plasticity. Dysregulated signaling underlies the pathogenesis of cancer, autoimmune disorders and metabolic diseases.
glycogen phosphorylase
The enzyme studied by Fischer and Krebs; it catalyzes the breakdown of glycogen to glucose-1-phosphate. The phosphorylated form (a) is highly active, whereas the dephosphorylated form (b) is less active, making it a textbook example of regulation by phosphorylation. During muscle exertion, rapid conversion to the a form boosts energy supply. The dimeric enzyme is also subject to allosteric control, serving as a classic model for metabolic regulation. It has regained attention as a potential diabetes drug target.
cAMP-dependent protein kinase (PKA)
A kinase activated by the second messenger cAMP, central to many hormone-response pathways. Activation occurs when catalytic subunits dissociate from regulatory subunits, enabling phosphorylation of hundreds of substrates. Fischer’s work implicated PKA in phosphorylating phosphorylase kinase, thereby controlling metabolism. Via phosphorylation of the CREB transcription factor, PKA also modulates gene expression and contributes to long-term memory formation. Aberrant PKA activity is implicated in endocrine tumors and heart failure.
post-translational modification
A collective term for chemical modifications occurring after protein synthesis, including phosphorylation, methylation, ubiquitination and more. PTMs alter function, oligomerization, localization and degradation rates, enhancing cellular responsiveness. Phosphorylation is the quintessential fast and reversible PTM. Advances in omics now allow dynamic mapping of PTM networks and aid biomarker discovery. Aberrant PTMs can cause signaling errors or protein aggregation, contributing to disease.
serine/threonine/tyrosine residues
Amino-acid side chains that are most commonly phosphorylated in proteins. Their hydroxyl (–OH) groups form ester bonds with the phosphate. Kinases recognize substrate consensus motifs and selectively phosphorylate these residues. Phosphorylation induces conformational and interface changes, toggling protein function. In mammals, serine/threonine phosphorylation is numerically dominant, but tyrosine phosphorylation often acts as a master key in signaling cascades.
pathophysiology
The field that investigates how disruption of normal physiology leads to disease. Abnormal phosphorylation causes diverse pathologies, including oncogenic over-proliferation, insulin resistance and neurodegeneration. Mutations in kinase genes or inhibition of phosphatases are frequent culprits. Understanding pathophysiology underpins targeted therapeutics and biomarker discovery. Fischer and Krebs provided the conceptual link between phosphorylation defects and disease, shaping modern biomedical research.