{"entity":{"id":"ubiquitin-proteasome-system","kind":"pathway","name":"Ubiquitin-proteasome system & protein homeostasis","aka":[],"tldr":"Cells tag unwanted proteins with a small marker called ubiquitin and feed them into a shredder, the proteasome. Myeloma cells, which make antibody in bulk, die if the shredder jams; and the newest drugs hijack the tagging machinery to make a cancer destroy its own oncoproteins.","summary":"E1 activates ubiquitin, E2 carries it, and one of ~600 E3 ligases (CRL4-CRBN, VHL, MDM2, SCF-FBXW7, APC/C) attaches it to a substrate lysine; K48 chains send substrates to the 26S proteasome, whose β5 subunit is the target of bortezomib, carfilzomib and ixazomib. Deubiquitinases (USP7, USP14) reverse tagging. Plasma cells and myeloma depend on proteasome capacity to clear misfolded immunoglobulin; inhibition triggers the unfolded protein response (PERK, IRE1, ATF6) and death, and stabilises IκB to shut NF-κB. Cereblon modulators (thalidomide, lenalidomide, pomalidomide; CELMoDs iberdomide, mezigdomide, golcadomide) are molecular glues that redirect CRL4-CRBN to degrade IKZF1/3. PROTACs (vepdegestrant for ER, ARV-766 for AR, BGB-16673 for BTK) link a target ligand to an E3 ligand. Oncogenic lesions in the system: FBXW7 loss stabilises MYC, cyclin E and NOTCH; SPOP mutations in prostate; VHL loss stabilises HIF; MDM2 amplification degrades p53. HSP90 and chaperones buffer mutant kinases; HSP90 inhibitors mostly failed on toxicity.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Proteasome","links":[{"label":"Békés, Langley & Crews, PROTAC targeted protein degraders: the past is prologue (Nat Rev Drug Discov 2022)","url":"https://doi.org/10.1038/s41573-021-00371-6"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":["multiple-myeloma","mantle-cell-lymphoma","prostate","breast-hr-positive"],"sections":[],"technologies":["protac-degrader","molecular-glue-platforms","degrader-antibody-conjugate"],"targets":["mdm2","hif2a","estrogen-receptor","btk","bcma","androgen-receptor"],"drugs":["bortezomib","carfilzomib","ixazomib","lenalidomide","pomalidomide","iberdomide","mezigdomide","golcadomide","vepdegestrant","bgb-16673"],"companies":[],"institutions":[],"pathways":["hif-vhl","p53-mdm2-axis","inflammation-nfkb","myc"],"terms":["r-iss","high-risk-myeloma"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-bekes-nat-rev-drug-discov"],"journals":[],"dependsOn":[],"notes":[],"analogy":"A recycling plant with barcode stickers (ubiquitin) and a shredder (proteasome). Myeloma is a paper mill that produces so much waste it dies when the shredder stops (bortezomib). PROTACs and glues are forged stickers that get the plant to shred the cancer's own machinery.","nodes":[{"id":"e1","label":"E1 → E2 ubiquitin","x":12,"y":15},{"id":"e3","label":"E3 ligase (CRBN, VHL, MDM2)","x":40,"y":15,"targetId":"mdm2"},{"id":"sub","label":"Substrate (IKZF1/3, p53, HIF)","x":70,"y":15,"targetId":"hif2a"},{"id":"chain","label":"K48 ubiquitin chain","x":70,"y":45},{"id":"dub","label":"DUBs (USP7)","x":92,"y":30},{"id":"prot","label":"26S proteasome (β5)","x":70,"y":75},{"id":"upr","label":"UPR, IκB → NF-κB","x":40,"y":75},{"id":"glue","label":"Glues / PROTACs hijack E3","x":40,"y":45,"targetId":"estrogen-receptor"},{"id":"deg","label":"Degradation","x":92,"y":90},{"id":"chap","label":"HSP90 chaperones","x":12,"y":75}],"edges":[{"from":"e1","to":"e3","type":"activates"},{"from":"e3","to":"sub","type":"activates"},{"from":"sub","to":"chain","type":"activates"},{"from":"dub","to":"chain","type":"inhibits"},{"from":"chain","to":"prot","type":"activates"},{"from":"prot","to":"deg","type":"activates"},{"from":"prot","to":"upr","type":"inhibits"},{"from":"glue","to":"e3","type":"activates"},{"from":"glue","to":"sub","type":"activates"},{"from":"chap","to":"sub","type":"inhibits"}],"interventions":["Proteasome inhibitors bortezomib, carfilzomib, ixazomib in multiple myeloma and mantle cell lymphoma","Cereblon glues: lenalidomide, pomalidomide; CELMoDs iberdomide, mezigdomide, golcadomide","PROTACs: vepdegestrant (ER), BGB-16673 (BTK), AR degraders; degrader-antibody conjugates deliver them by antibody","Reactivating degradation of oncoproteins (MDM2 inhibition for p53) and blocking DUBs are in trials"]},"route":"/pathways/ubiquitin-proteasome-system/","neighbours":{"cancer":[{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"mantle-cell-lymphoma","kind":"cancer","name":"Mantle cell lymphoma","route":"/cancers/mantle-cell-lymphoma/"},{"id":"multiple-myeloma","kind":"cancer","name":"Multiple myeloma","route":"/cancers/multiple-myeloma/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"technology":[{"id":"degrader-antibody-conjugate","kind":"technology","name":"Degrader-antibody conjugate (DAC)","route":"/technologies/degrader-antibody-conjugate/"},{"id":"molecular-glue-platforms","kind":"technology","name":"Molecular glue discovery platforms","route":"/technologies/molecular-glue-platforms/"},{"id":"protac-degrader","kind":"technology","name":"PROTACs & molecular glues (targeted protein degradation)","route":"/technologies/protac-degrader/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"bcma","kind":"target","name":"BCMA","route":"/targets/bcma/"},{"id":"btk","kind":"target","name":"BTK (Bruton tyrosine kinase)","route":"/targets/btk/"},{"id":"estrogen-receptor","kind":"target","name":"Estrogen receptor (ERα)","route":"/targets/estrogen-receptor/"},{"id":"hif2a","kind":"target","name":"HIF-2α","route":"/targets/hif2a/"},{"id":"hsp90aa1","kind":"target","name":"HSP90AA1","route":"/targets/hsp90aa1/"},{"id":"ikzf1","kind":"target","name":"IKZF1 (Ikaros)","route":"/targets/ikzf1/"},{"id":"ikzf3","kind":"target","name":"IKZF3 (Aiolos)","route":"/targets/ikzf3/"},{"id":"mdm2","kind":"target","name":"MDM2","route":"/targets/mdm2/"},{"id":"usp7","kind":"target","name":"USP7","route":"/targets/usp7/"},{"id":"vhl","kind":"target","name":"VHL","route":"/targets/vhl/"}],"drug":[{"id":"bgb-16673","kind":"drug","name":"BGB-16673","route":"/drugs/bgb-16673/"},{"id":"bortezomib","kind":"drug","name":"Bortezomib","route":"/drugs/bortezomib/"},{"id":"carfilzomib","kind":"drug","name":"Carfilzomib","route":"/drugs/carfilzomib/"},{"id":"golcadomide","kind":"drug","name":"Golcadomide","route":"/drugs/golcadomide/"},{"id":"iberdomide","kind":"drug","name":"Iberdomide","route":"/drugs/iberdomide/"},{"id":"ixazomib","kind":"drug","name":"Ixazomib","route":"/drugs/ixazomib/"},{"id":"lenalidomide","kind":"drug","name":"Lenalidomide","route":"/drugs/lenalidomide/"},{"id":"mezigdomide","kind":"drug","name":"Mezigdomide","route":"/drugs/mezigdomide/"},{"id":"pomalidomide","kind":"drug","name":"Pomalidomide","route":"/drugs/pomalidomide/"},{"id":"vepdegestrant","kind":"drug","name":"Vepdegestrant","route":"/drugs/vepdegestrant/"}],"pathway":[{"id":"inflammation-nfkb","kind":"pathway","name":"Inflammation & NF-κB","route":"/pathways/inflammation-nfkb/"},{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"},{"id":"p53-mdm2-axis","kind":"pathway","name":"The p53 network (guardian of the genome)","route":"/pathways/p53-mdm2-axis/"},{"id":"hif-vhl","kind":"pathway","name":"VHL / HIF oxygen sensing","route":"/pathways/hif-vhl/"}],"term":[{"id":"high-risk-myeloma","kind":"term","name":"High-risk cytogenetics (myeloma)","route":"/terms/high-risk-myeloma/"},{"id":"r-iss","kind":"term","name":"R-ISS / R2-ISS staging","route":"/terms/r-iss/"}],"paper":[{"id":"paper-barbieri-spop-foxa1-med12-prostate-nat-genet-2012","kind":"paper","name":"Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer","route":"/key-papers/paper-barbieri-spop-foxa1-med12-prostate-nat-genet-2012/"},{"id":"paper-bekes-nat-rev-drug-discov","kind":"paper","name":"PROTAC targeted protein degraders: the past is prologue","route":"/key-papers/paper-bekes-nat-rev-drug-discov/"},{"id":"paper-tcga-molecular-taxonomy-primary-prostate-cell-2015","kind":"paper","name":"TCGA: the molecular taxonomy of primary prostate cancer","route":"/key-papers/paper-tcga-molecular-taxonomy-primary-prostate-cell-2015/"},{"id":"paper-armenia-long-tail-oncogenic-drivers-prostate-nat-genet-2018","kind":"paper","name":"The long tail of oncogenic drivers in prostate cancer","route":"/key-papers/paper-armenia-long-tail-oncogenic-drivers-prostate-nat-genet-2018/"},{"id":"paper-wu-pancreatic-cyst-exomes-rnf43-pnas-2011","kind":"paper","name":"Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways","route":"/key-papers/paper-wu-pancreatic-cyst-exomes-rnf43-pnas-2011/"}],"biomarker":[{"id":"spop-mutation","kind":"biomarker","name":"SPOP mutation","route":"/biomarkers/spop-mutation/"}]}}