MassIVEapplication/xmlftp://massive-ftp.ucsd.edu/v06/MSV000096874/primaryOK200ProteomicsPatrick Ryan PottsOrbitrap EclipsetimsTOF HTHomo Sapiens (ncbitaxon:9606)https://massive.ucsd.edu/ProteoSAFe/dataset.jsp?task=20a73984ae0749c69399b1771b5472dbrpotts01@amgen.comAmgen Inc.MassIVE226UNIMOD:4 - "Iodoacetamide derivative."small, biochemical pathways, single-organism catabolic process, multicellular organismal catabolic process, cellular breakdown, LAMP Lysosomal-Associated Membrane Protein, Lysosome Associated Membrane Glycoprotein, Lysosome Associated Membrane Glycoproteins, Lysosomal-Associated, degradation, protein complex, Proteins, Lysosomal Associated Membrane Protein, Gene, Lysosomal Membrane Glycoproteins, protein, neutral molecular compounds, protein-containing complex, Membrane Glycoproteins, Lysosomal Membrane Protein, Lysosome-Associated Membrane Glycoproteins, cellular catabolism, Lysosome-Associated, Lysosome-Associated Membrane Glycoprotein, Lysosomal Membrane Glycoprotein, protein polypeptide chains, Lysosomal-Associated Membrane Proteins, native protein, reduced, natural protein, polypeptide chain, LAMP Lysosomal Associated Membrane Proteins, Protein, Membrane Proteins, Gene Products, cellular degradation, secretion, tiny, protein aggregate, Lysosomal-Associated Membrane Protein, molecule, Lysosomal Associated Membrane Proteins, molecula, molecules, breakdown, biodegradation, underdeveloped, breakdown of molecule., breakdown of chemical, catabolism, Lysosomal, LAMP Lysosomal Associated Membrane Protein, hypoplasia, Lysosome Associated Membrane Proteins, proteins, Molekuel, Lysosomal Integral Membrane Protein, Protein Gene Products, Gene Proteins, breakdown of substance, LAMP Lysosomal-Associated Membrane Proteins, Membrane Glycoprotein, Lysosome-Associated Membrane Protein, Lysosome-Associated Membrane Proteins, Lysosomal Integral Membrane Proteins, biotransformation, Membrane Protein, Lysosome Associated Membrane Proteinsingle-organism 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EG:EG0002.1, K-RAS2B, K-RAS2A, Proteins, stress-activated kinase activity, MAP-2 kinase activity, Cell Surface, Cell Surface Protein, c-Ki-ras, Cell, native protein, stress-activated protein kinase activity, mapk2, chemical analysis, mapk1, anatomical spaces, Tcf/LEF, Lysosomal Associated Membrane Proteins, Cell Surface Proteins, Membrane Associated Protein, periarteritis, lumen space, NS, CG12559, underdeveloped, P42MAPK, dpERK1, postnatal growth, Itpr-1, CG32005, extracellular, Gene Proteins, AU018647, signalling process, pharmacologic action, dpMAPK, Lef, SAP kinase activity, biochemical pathways, multicellular organismal catabolic process, Integral Membrane Proteins, Ip3r, mode of action, pharmacodynamics, Polyarteritis Nodosa, determination, Mpk2, postnatal development, Surface Proteins, p42mapk, DmelCG34403, Membrane-Associated Proteins, protein, neutral molecular compounds, IA5, SR2-1, Membrane Tissues, cellular degradation, mitogen-activated protein kinase activity, protein aggregate, mpk1, molecule, k-ras, molecula, rask2, TCF/LEF, Erk/Map kinase, membrane region, LAMP Lysosomal Associated Membrane Protein, hypoplasia, DERK-A, E(sina)7, Lysosomal Integral Membrane Protein, Rl, MP kinase activity, LAMP Lysosomal-Associated Membrane Proteins, DERK, Lysosome-Associated Membrane Protein, disease management, MBP kinase II activity, Therapies, biotransformation, Membrane Associated Proteins, dERK, necrosis, Membrane Protein, polyarteritis, ATP, Therapy, Membrane Tissue, MAP kinase 2 activity, Mapk, Ki-ras, Arts, OPT, Erk1, ERK1, InsP3R, ERK2, mapk1a, Erk2, membranous organ component, LEF/TCF, Dm Pan, p41mapk, inhibition of kinase activity, mapk1b, MapK, MAPK, PERIANTHIA, p21, lethal type, opt, internal to cell, erk2, mapk, P400, ERKa, Transphosphorylases, Protein enigma, membrane of organ, BcDNA:RE08694, pterygium syndrome multiple lethal type, l(2R)EMS45-39, CAPB, DmelCG12559, p38, CG17964, Treatments, DpErk, DpERK, ErkA, ERKA, p41, p40, LMP, Proteomes, pERK, 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membrane, Membrane Proteins, MBP kinase I activity, Tcf, TCF, Pcp-1, AI929937, breakdown of molecule, Xp42, Lef1, transmembrane, LEF1, biodegradation, mitogen activated kinase activity, Kinases, Su(Raf)2B, EY2-2, tcf, MAPK2, Membrane, OPT1, l(4)102ABb, Protein Gene Products, breakdown of substance, Integral Membrane Protein, D-ERK, Therapeutic, opt1, ERT1, kras, DmelCG2913, CFC2, EPHT3, Lysosome-Associated Membrane Proteins, Lysosomal Integral Membrane Proteins, Treatment, assay, lef1, growth, Agkistrodon contortrix contortrix protein C activator, MAP kinase 1 activity, Lysosome Associated Membrane ProteinfalseLYMTACs: Chimeric Small Molecules Repurpose Lysosomal Membrane Proteins for Target Protein Relocalization and DegradationProximity-inducing modalities that co-opt cellular pathways offer new opportunities to regulate oncogenic drivers. Inspired by the success of proximity-based chimeras in both intracellular and extracellular target space, here we describe the development of LYsosome Membrane TArgeting Chimeras (LYMTACs) as a novel small molecule-based platform that functions intracellularly to modulate the membrane proteome. Conceptually, LYMTACs are heterobifunctional small molecules that co-opt short-lived lysosomal membrane proteins (LMPs) as effectors to deliver targets for lysosomal degradation. We demonstrate that a promiscuous kinase inhibitor-based LYMTAC selectively targets membrane proteins for lysosomal degradation via RNF152, a short-lived LMP. To extend these findings, we show that oncogenic, membrane-associated KRASG12D protein can be tethered to RNF152, inducing KRAS relocalization to the lysosomal membrane, inhibiting downstream phospho-ERK signaling, and leading to lysosomal degradation of KRASG12D in a LYMTAC-dependent manner. Notably, potent cell killing could be attributed to the multi-pharmacology displayed by LYMTACs, which differentiates the LYMTAC technology from existing modalities. Thus, LYMTACs represent a proximity-based therapeutic approach that promises to expand the target space for challenging membrane proteins through targeted protein relocalization and degradation. The dataset is global proteomics analysis of pan kinase PROTAC or LYMTAC treated cells.Thu Jan 16 12:55:00 GMT 2025MSV000096874