TABLE 1.
Representative phosphorylation events in health and diseases.
| Diseases and biological processes | Protein substrates | Effects | |
|---|---|---|---|
| Aging | αB‐crystallin | αB‐crystallin phosphorylation increases in muscle tissues and eye lens with age. 96 , 97 | |
| p53 | Phosphorylation of p53 DNA‐binding domain reduces p53 activity and prevents senescence. 98 | ||
| MDM2 phosphorylation at Ser183 activates p53‐mediated senescence and delays tumor progression. 100 | |||
| B50/GAP‐43 protein | Phosphorylation B50/GAP‐43 is critical for long‐term memory and reduced in the hippocampus of aging rats. 193 | ||
| Tau | Accumulation of Tau phosphorylation at Ser396/404 in mitochondria contributes to cognitive dysfunction during aging. 104 | ||
| mTORC1 | Basal mTORC1 hyperphosphorylation in the elderly may contribute to insulin resistance and the age‐related anabolic resistance of skeletal muscle protein metabolism to nutrition and exercise. 107 | ||
| RLC | Decreased phosphorylation of RLC at Ser14/15 with age causes sarcopenia‐associated muscle dysfunction. 108 | ||
| Development | MeCP2 | S421 phosphorylation controls the ability of MeCP2 to regulate dendritic patterning, spine morphogenesis, and the activity‐dependent induction. 194 | |
| AKT1 | EGF promotes AKT1 phosphorylation, which further stimulates the proliferation of stem cells and precursor mesenchymal cells while blocks their differentiation. 195 | ||
| MSY2 | Phosphorylation of the MSY2 drives maternal mRNA degradation and converts a highly differentiated oocyte to totipotent blastomeres. 196 | ||
| Immune regulation | Infection | STAT1 | Serine phosphorylation of STAT1 is required for the body's resistance to viral infection. 115 |
| STAT6 | STAT6 regulates the innate immunity by transducing signals from extracellular cytokines through phosphorylation by TBK1. 119 | ||
| STAT2 | STAT2 phosphorylation at S734 inhibits IFN‐α‐induced antiviral responses. 120 | ||
| TRAF4 | TRAF4 phosphorylation downregulates innate immune signaling. 197 | ||
| STING | Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. 198 | ||
| NF‐κB | NF‐κB activation regulated by phosphorylation controls the expression of a series of inflammatory cytokine genes and triggers the antiviral innate immune response. 199 | ||
| MAVS | Phosphorylation of MAVS and STING by IKK/TBK1 induces type‐I IFNs and other antiviral molecules. 117 | ||
| MITA | MITA phosphorylation by TBK1 during antiviral immunity activates IRF3. 200 | ||
| YAP | Viruses activate the kinase IKKε to further phosphorylates YAP at Ser403 and trigger YAP degradation to antagonize innate antiviral immunity. 121 | ||
| Tumor immunology | RAB7 | RAB7 phosphorylation by TBK1/IKKε regulates innate immune signaling in triple‐negative breast cancer. 201 | |
| PDHE1α | Phosphorylated PDHE1α at S327 by ERK2 in cytoplasm can induce its transfer to mitochondria and improve NF‐κB signal in the cytoplasm, which increases resistance to cytotoxic lymphocytes and promotes tumor immune escape. 125 | ||
| IκBα | In GBM, HK2 binds to IκBα and phosphorylates it at Thr291, which increases PD‐L1 expression and promotes tumor immune escape. 126 | ||
| p73 | CDK4/6 of tumor cells phosphorylate p53 family member p73 to prevent DR5 activation and promote antitumor immunity. 202 | ||
| NEDD4 | In urothelial carcinoma, activated FGFR3 phosphorylates NEDD4 and further regulates Lys48‐linked ubiquitination of PD‐L1 to activate CD8+ T cell infiltration and antitumor activity. 203 | ||
| METTL3 | TBK1 phosphorylates m6A methyltransferase METTL3 to enhance the interaction between METTL3 and the translation complex, which promotes antitumor immune response. 204 | ||
| Metabolic disorders | DM | GLP1 | Phosphorylation at Arg91 may inhibit processing of glucagon precursor to GLP1 to affect the blood glucose levels. 132 |
| PPARγ | Phosphorylation of PPARγ at S273 induces insulin resistance by upregulating Gdf3 expression and inhibiting BMP signaling pathway. 133 | ||
| Afadin | Phosphorylation of Afadin at S1795 promotes insulin resistance in the early stages of diet‐induced obesity. 134 | ||
| Obesity | PPARγ | Blocking PPARγ phosphorylation at Thr166 prevents obesity‐related metabolic dysfunction. 138 | |
| Cancers | Multiple cancers | HK1 | c‐Src phosphorylates HK1 at Tyr732 to promote the glycolysis rate of tumor cells and their proliferation, invasion, and metastasis abilities. 71 |
| Multiple cancers | IκBα | Aerobic glycolysis promotes tumor immune escape through phosphorylation of IκBα at T291 mediated by HK2. 126 | |
| Breast cancer | HK2 | Phosphorylation of HK2 at Thr473 by PIM2 enhances HK2 stability and activity and promotes glycolysis, tumor growth, and drug resistance to paclitaxel. 165 | |
| Glioma | PFKP | Phosphorylation of PFKP by AKT at Ser386 inhibits PFKP degradation and promotes aerobic glycolysis of glioma cells and tumor growth. 167 | |
| Melanoma | PFKFB2 | RSK phosphorylates PFKFB2 to increase PFKFB2 activity and the glycolysis pathway, which accelerates the growth of BRAF‐mutated melanoma. 168 | |
| Multiple cancers | PKM2 | Phosphorylation of PKM2 at Tyr105 mediates the transformation of tumor cell metabolic mode to aerobic glycolysis. 170 | |
| Multiple cancers | PDHA | Hyperphosphorylation of PDHA at Ser295 and Ser314 redirects tumor metabolism to TCA cycle. This protects spread cancer cells from metabolic and oxidative stress‐induced cell death and promotes tumor metastasis. 171 | |
| Gastric cancer | ULK1 | DAPK3 directly phosphorylates Ser556 of ULK1 to increase ULK1 activity and promote the formation of ULK1 complex, leading to inhibition of the proliferation of gastric cancer cells. 173 | |
| GBM | ACSS2 | Phosphorylation at Ser267 of ACSS2 by CDK5 inhibits the degradation of ACSS2 and promote the growth of GBM tumor cells. 174 | |
| Colon cancer | Drp | ERK phosphorylates Drp1 at Ser616 to activate it. Activated Drp1 facilitates the oxidation of fatty acids to promote the proliferation of colon cancer cells. 176 | |
| Breast cancer | RNF12 | AKT promotes TGF‐β‐driven breast cancer metastasis by mediating RNF12 phosphorylation and enhancing RNF12 stability. 177 | |
| Bladder cancer | AKT | KNSTRN phosphorylates AKT at Thr308 and Ser473 to activate AKT and promotes bladder cancer metastasis. 178 | |
| Breast cancer | PKM2 | Phosphorylation of PKM2 at Ser37 is a prominent feature of invasive breast cancer. 180 | |
| PC | PD‐L1 | NEK2 phosphorylates PD‐L1 at Thr194/Thr210 to maintain its stability, leading to less effectiveness of PD‐L1‐targeted therapy in PC. 205 | |
| Neurodegenerative diseases | PD | Parkin | Dyrk1A phosphorylates Parkin at Ser131 to inhibit its E3 Ub ligase activity, which may be involved in the pathogenesis of PD. 206 |
| XBP1s | PINK1 can control XBP1s transcriptional activity by phosphorylating XBP1s at Ser61 and The48, which consequently enhances PINK1's own transcription. 186 | ||
| AD | Tau | Transient Tau hyperphosphorylation has a protective effect on neurons. While persistent accumulation of phosphorylated Tau causes neurodegeneration. 189 Hyperphosphorylated Tau depolymerizes normal microtubule‐associated proteins after forming neuronfibrillary tangle, disrupts cellular dynamic structures, blocks intracellular material exchange and cell signaling, inhibits Ub–proteasome activity. 190 , 191 | |
Abbreviations: AD, Alzheimer's disease; DM, diabetes mellitus; GBM, glioblastoma; PC, pancreatic cancer; PD, Parkinson's disease; RLC, regulatory light chain.