Versatility of 14-3-3 proteins and their roles in bone and joint-related diseases

Abstract

Bone and joint-related diseases, including osteoarthritis (OA), rheumatoid arthritis (RA), and bone tumors, pose significant health challenges due to their debilitating effects on the musculoskeletal system. 14-3-3 proteins, a family of conserved regulatory molecules, play a critical role in the pathology of these diseases. This review discusses the intricate structure and multifunctionality of 14-3-3 proteins, their regulation of signaling pathways, and their interactions with other proteins. We underscore the significance of 14-3-3 proteins in the regulation of osteoblasts, osteoclasts, chondrocytes, and bone remodeling, all key factors in the maintenance and dysfunction of bone and joint systems. Specific focus is directed toward elucidating the contribution of 14-3-3 proteins in the pathology of OA, RA, and bone malignancies, where dysregulated 14-3-3-mediated signaling cascades have been implicated in the disease processes. This review illuminates how the perturbation of 14-3-3 protein interactions can lead to the pathological manifestations observed in these disorders, including joint destruction and osteolytic activity. We highlight cutting-edge research that positions 14-3-3 proteins as potential biomarkers for disease progression and as innovative therapeutic targets, offering new avenues for disease intervention and management.

References

[1.] Weng, Q. et al. Global burden of early-onset osteoarthritis, 1990–2019: results from the Global Burden of Disease Study 2019. Ann. Rheum. Dis.83, 915–925 (2024).

[2.] SebbagE, et al. . The worldwide burden of musculoskeletal diseases: a systematic analysis of the World Health Organization burden of diseases database. Ann. Rheum. Dis., 2019, 78: 844-848

[3.] FuW, et al. . Na(v)1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis. Nature, 2024, 625: 557-565

[4.] QinL, et al. . Roles of mechanosensitive channel Piezo1/2 proteins in skeleton and other tissues. Bone Res., 2021, 9: 44

[5.] WuX, et al. . Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis. Nat. Aging, 2022, 2: 332-347

[6.] TangW, et al. . The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science, 2011, 332: 478-484

[7.] Glyn-JonesS, et al. . Osteoarthritis. Lancet, 2015, 386: 376-387

[8.] Moore, B. W. & Perez, V. J. Specific acidic proteins of the nervous system. Osteoarthritis and Cartilage/OARS, Osteoarthritis Research Society ed. F. D. Carlson, 343–359 (Prentice-Hall, 1967).

[9.] AitkenA. 14-3-3 proteins: a historic overview. Semin. Cancer Biol., 2006, 16: 162-172

[10.] GardinoAK, SmerdonSJ, YaffeMB. Structural determinants of 14-3-3 binding specificities and regulation of subcellular localization of 14-3-3-ligand complexes: a comparison of the X-ray crystal structures of all human 14-3-3 isoforms. Semin. Cancer Biol., 2006, 16: 173-182

[11.] CauY, ValensinD, MoriM, DraghiS, BottaM. Structure, function, involvement in diseases and targeting of 14-3-3 proteins: an update. Curr. Med. Chem., 2018, 25: 5-21

[12.] CelisJE, et al. . Comprehensive two-dimensional gel protein databases offer a global approach to the analysis of human cells: the transformed amnion cells (AMA) master database and its link to genome DNA sequence data. Electrophoresis, 1990, 11: 989-1071

[13.] FuH, SubramanianRR, MastersSC. 14-3-3 proteins: structure, function, and regulation. Annu. Rev. Pharmacol. Toxicol., 2000, 40: 617-647

[14.] SkoulakisEM, DavisRL. 14-3-3 proteins in neuronal development and function. Mol. Neurobiol., 1998, 16: 269-284

[15.] JiaY, et al. . Targeting macrophage TFEB-14-3-3 epsilon Interface by naringenin inhibits abdominal aortic aneurysm. Cell Discov., 2022, 8: 21

[16.] ZhangY, et al. . 14-3-3epsilon: a protein with complex physiology function but promising therapeutic potential in cancer. Cell Commun. Signal., 2024, 22: 72

[17.] YaffeMB, et al. . The structural basis for 14-3-3:phosphopeptide binding specificity. Cell, 1997, 91: 961-971

[18.] ObsilovaV, ObsilT. Structural insights into the functional roles of 14-3-3 proteins. Front. Mol. Biosci., 2022, 9

[19.] LowZY, YipAJW, ChanAML, ChooWS. 14-3-3 family of proteins: biological implications, molecular interactions, and potential intervention in cancer, virus, and neurodegeneration disorders. J. Cell. Biochem., 2024, 125

[20.] SteversLM, et al. . Modulators of 14-3-3 protein-protein interactions. J. Med. Chem., 2018, 61: 3755-3778

[21.] SluchankoNN, BustosDM. Intrinsic disorder associated with 14-3-3 proteins and their partners. Prog. Mol. Biol. Transl. Sci., 2019, 166: 19-61

[22.] RiveroG, et al. . 14-3-3epsilon protein-immobilized PCL-HA electrospun scaffolds with enhanced osteogenicity. J. Mater. Sci. Mater. Med., 2019, 30: 99

[23.] KimH, et al. . Selenoprotein W ensures physiological bone remodeling by preventing hyperactivity of osteoclasts. Nat. Commun., 2021, 12

[24.] YoonHE, KimKS, KimIY. 14-3-3 eta inhibits chondrogenic differentiation of ATDC5 cell. Biochem. Biophys. Res. Commun., 2011, 406: 59-63

[25.] TazawaH, TakahashiS, ZilliacusJ. Interaction of the parathyroid hormone receptor with the 14-3-3 protein. Biochim. Biophys. Acta, 2003, 1620: 32-38

[26.] Fu, W. et al. TNFR2/14-3-3epsilon signaling complex instructs macrophage plasticity in inflammation and autoimmunity. J. Clin. Investig.131, e144016 (2021).

[27.] WuQ, ZhuJ, LiuF, LiuJ, LiM. Downregulation of 14-3-3beta inhibits proliferation and migration in osteosarcoma cells. Mol. Med. Rep., 2018, 17: 2493-2500

[28.] GongX, et al. . Elevated serum 14-3-3eta protein may be helpful for diagnosis of early rheumatoid arthritis associated with secondary osteoporosis in Chinese population. Clin. Rheumatol., 2017, 36: 2581-2587

[29.] FuW, et al. . 14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis. Ann. Rheum. Dis., 2021, 80: 1615-1627

[30.] MillerandM, et al. . Activation of innate immunity by 14-3-3 epsilon, a new potential alarmin in osteoarthritis. Osteoarthr. Cartil., 2020, 28: 646-657

[31.] TrimovaG, et al. . Tumour necrosis factor-alpha promotes secretion of 14-3-3eta by inducing necroptosis in macrophages. Arthritis Res. Ther., 2020, 22: 24

[32.] YangX, et al. . Structural basis for protein-protein interactions in the 14-3-3 protein family. Proc. Natl. Acad. Sci. USA, 2006, 103: 17237-17242

[33.] ObsilT, ObsilovaV. Structural basis of 14-3-3 protein functions. Semin. Cell Dev. Biol., 2011, 22: 663-672

[34.] HalskauOJr., et al. . Three-way interaction between 14-3-3 proteins, the N-terminal region of tyrosine hydroxylase, and negatively charged membranes. J. Biol. Chem., 2009, 284: 32758-32769

[35.] AbdiG, et al. . 14-3-3 proteins-a moonlight protein complex with therapeutic potential in neurological disorder: in-depth review with Alzheimer’s disease. Front. Mol. Biosci., 2024, 11

[36.] DarlingDL, YinglingJ, Wynshaw-BorisA. Role of 14-3-3 proteins in eukaryotic signaling and development. Curr. Top. Dev. Biol., 2005, 68: 281-315

[37.] MunierCC, OttmannC, PerryMWD. 14-3-3 modulation of the inflammatory response. Pharmacol. Res., 2021, 163

[38.] MuslinAJ, TannerJW, AllenPM, ShawAS. Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine. Cell, 1996, 84: 889-897

[39.] MannJ, et al. . Non-canonical BAD activity regulates breast cancer cell and tumor growth via 14-3-3 binding and mitochondrial metabolism. Oncogene, 2019, 38: 3325-3339

[40.] SadikG, et al. . Phosphorylation of tau at Ser214 mediates its interaction with 14-3-3 protein: implications for the mechanism of tau aggregation. J. Neurochem., 2009, 108: 33-43

[41.] Obsilova, V. & Obsil, T. The 14-3-3 Proteins as important allosteric regulators of protein kinases. Int. J. Mol. Sci.21, 8824 (2020).

[42.] KongsamutS, EishingdreloH. Modulating GPCR and 14-3-3 protein interactions: prospects for CNS drug discovery. Drug Discov. Today, 2023, 28

[43.] EishingdreloH, QinX, YuanL, KongsamutS, YuL. Ligands can differentially and temporally modulate GPCR interaction with 14-3-3 isoforms. Curr. Res. Pharmacol. Drug Discov., 2022, 3

[44.] FerlRJ, ManakMS, ReyesMF. The 14-3-3s. Genome Biol., 2002, 3

[45.] Vigneswara, V. & Ahmed, Z. The role of caspase-2 in regulating cell fate. Cells9, 1259 (2020).

[46.] RamakrishnanG, et al. . AKT and 14-3-3 regulate Notch4 nuclear localization. Sci. Rep., 2015, 5

[47.] SeifF, et al. . The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun. Signal, 2017, 15

[48.] VillarinoAV, KannoY, O’SheaJJ. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat. Immunol., 2017, 18: 374-384

[49.] KacirovaM, NovacekJ, ManP, ObsilovaV, ObsilT. Structural Basis for the 14-3-3 protein-dependent inhibition of phosducin function. Biophys. J., 2017, 112: 1339-1349

[50.] Agarwal-MawalA, et al. . 14-3-3 connects glycogen synthase kinase-3 beta to tau within a brain microtubule-associated tau phosphorylation complex. J. Biol. Chem., 2003, 278: 12722-12728

[51.] HuangX, et al. . 14-3-3 proteins are potential regulators of liquid-liquid phase separation. Cell Biochem. Biophys., 2022, 80: 277-293

[52.] MastersSC, et al. . Survival-promoting functions of 14-3-3 proteins. Biochem. Soc. Trans., 2002, 30: 360-365

[53.] LiuJ, et al. . The role of 14-3-3 proteins in cell signalling pathways and virus infection. J. Cell Mol. Med., 2021, 25: 4173-4182

[54.] Yuan, R. et al. Chk1 and 14-3-3 proteins inhibit atypical E2Fs to prevent a permanent cell cycle arrest. EMBO J.37, e97877 (2018).

[55.] ZhouY, et al. . 1,3-Dicaffeoylquinic acid targeting 14-3-3 tau suppresses human breast cancer cell proliferation and metastasis through IL6/JAK2/PI3K pathway. Biochem. Pharm., 2020, 172

[56.] YeDZ, JinS, ZhuoY, FieldJ. p21-Activated kinase 1 (Pak1) phosphorylates BAD directly at serine 111 in vitro and indirectly through Raf-1 at serine 112. PLoS One, 2011, 6: e27637

[57.] YanY, et al. . Implication of 14-3-3epsilon and 14-3-3theta/tau in proteasome inhibition-induced apoptosis of glioma cells. Cancer Sci., 2013, 104: 55-61

[58.] SunZ, et al. . 14-3-3zeta targets beta-catenin nuclear translocation to maintain mitochondrial homeostasis and promote the balance between proliferation and apoptosis in cisplatin-induced acute kidney injury. Cell Signal., 2023, 111

[59.] ShenQ, et al. . Overexpression of the 14-3-3gamma protein in uterine leiomyoma cells results in growth retardation and increased apoptosis. Cell Signal., 2018, 45: 43-53

[60.] LevineB, KroemerG. Biological functions of autophagy genes: a disease perspective. Cell, 2019, 176: 11-42

[61.] TangY, et al. . 14-3-3zeta binds to and stabilizes phospho-beclin 1(S295) and induces autophagy in hepatocellular carcinoma cells. J. Cell Mol. Med., 2020, 24: 954-964

[62.] ZhengZ, ZhongQ, YanX. YWHAE/14-3-3epsilon crotonylation regulates leucine deprivation-induced autophagy. Autophagy, 2023, 19: 2401-2402

[63.] RobichaudS, et al. . Identification of novel lipid droplet factors that regulate lipophagy and cholesterol efflux in macrophage foam cells. Autophagy, 2021, 17: 3671-3689

[64.] KleppeR, MartinezA, DoskelandSO, HaavikJ. The 14-3-3 proteins in regulation of cellular metabolism. Semin. Cell Dev. Biol., 2011, 22: 713-719

[65.] MeekSE, LaneWS, Piwnica-WormsH. Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins. J. Biol. Chem., 2004, 279: 32046-32054

[66.] BentonR, PalaciosIM, St JohnstonD. Drosophila 14-3-3/PAR-5 is an essential mediator of PAR-1 function in axis formation. Dev. Cell, 2002, 3: 659-671

[67.] DingJ, et al. . 14-3-3zeta is involved in the anticancer effect of metformin in colorectal carcinoma. Carcinogenesis, 2018, 39: 493-502

[68.] TongY, et al. . KAT2A succinyltransferase activity-mediated 14-3-3zeta upregulation promotes beta-catenin stabilization-dependent glycolysis and proliferation of pancreatic carcinoma cells. Cancer Lett., 2020, 469: 1-10

[69.] PhanL, et al. . The cell cycle regulator 14-3-3sigma opposes and reverses cancer metabolic reprogramming. Nat. Commun., 2015, 6

[70.] ThorsonJA, et al. . 14-3-3 proteins are required for maintenance of Raf-1 phosphorylation and kinase activity. Mol. Cell. Biol., 1998, 18: 5229-5238

[71.] FischerA, et al. . Regulation of RAF activity by 14-3-3 proteins: RAF kinases associate functionally with both homo- and heterodimeric forms of 14-3-3 proteins. J. Biol. Chem., 2009, 284: 3183-3194

[72.] ShaulYD, SegerR. The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim. Biophys. Acta, 2007, 1773: 1213-1226

[73.] XingH, ZhangS, WeinheimerC, KovacsA, MuslinAJ. 14-3-3 proteins block apoptosis and differentially regulate MAPK cascades. EMBO J., 2000, 19: 349-358

[74.] Nordgaard, C. et al. Regulation of the Golgi apparatus by p38 and jnk kinases during cellular stress responses. Int. J. Mol. Sci.22, 9595 (2021).

[75.] Gomez-SuarezM, et al. . 14-3-3 Proteins regulate Akt Thr308 phosphorylation in intestinal epithelial cells. Cell Death Differ., 2016, 23: 1060-1072

[76.] MuslinAJ, XingH. 14-3-3 proteins: regulation of subcellular localization by molecular interference. Cell Signal., 2000, 12: 703-709

[77.] TzivionG, DobsonM, RamakrishnanG. FoxO transcription factors; Regulation by AKT and 14-3-3 proteins. Biochim. Biophys. Acta, 2011, 1813: 1938-1945

[78.] NealCL, et al. . Overexpression of 14-3-3zeta in cancer cells activates PI3K via binding the p85 regulatory subunit. Oncogene, 2012, 31: 897-906

[79.] Ursini-SiegelJ, et al. . The ShcA SH2 domain engages a 14-3-3/PI3’K signaling complex and promotes breast cancer cell survival. Oncogene, 2012, 31: 5038-5044

[80.] SuYW, et al. . 14-3-3sigma regulates B-cell homeostasis through stabilization of FOXO1. Proc. Natl. Acad. Sci. USA, 2011, 108: 1555-1560

[81.] Hata, A. & Chen, Y. G. TGF-beta signaling from receptors to Smads. Cold Spring Harb. Perspect. Biol.8, a022061 (2016).

[82.] ZakharchenkoO, CojocM, DubrovskaA, SouchelnytskyiS. A role of TGFss1 dependent 14-3-3sigma phosphorylation at Ser69 and Ser74 in the regulation of gene transcription, stemness, and radioresistance. PloS One, 2013, 8: e65163

[83.] PengD, FuM, WangM, WeiY, WeiX. Targeting TGF-beta signal transduction for fibrosis and cancer therapy. Mol. Cancer, 2022, 21

[84.] DovratS, et al. . 14-3-3 and beta-catenin are secreted on extracellular vesicles to activate the oncogenic Wnt pathway. Mol. Oncol., 2014, 8: 894-911

[85.] LaiXJ, et al. . Selective 14-3-3gamma induction quenches p-beta-catenin Ser37/Bax-enhanced cell death in cerebral cortical neurons during ischemia. Cell Death Dis., 2014, 5: e1184

[86.] ChangTC, et al. . 14-3-3sigma regulates beta-catenin-mediated mouse embryonic stem cell proliferation by sequestering GSK-3beta. PloS One, 2012, 7: e40193

[87.] ValentaT, HausmannG, BaslerK. The many faces and functions of beta-catenin. EMBO J., 2012, 31: 2714-2736

[88.] KoelmanEMR, Yeste-VazquezA, GrossmannTN. Targeting the interaction of beta-catenin and TCF/LEF transcription factors to inhibit oncogenic Wnt signaling. Bioorg. Med. Chem., 2022, 70

[89.] FreemanAK, MorrisonDK. 14-3-3 Proteins: diverse functions in cell proliferation and cancer progression. Semin. Cell Dev. Biol., 2011, 22: 681-687

[90.] SchlegelmilchK, et al. . Yap1 acts downstream of alpha-catenin to control epidermal proliferation. Cell, 2011, 144: 782-795

[91.] HabbigS, et al. . NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway. J. Cell Biol., 2011, 193: 633-642

[92.] ZuoS, et al. . 14-3-3 epsilon dynamically interacts with key components of mitogen-activated protein kinase signal module for selective modulation of the TNF-alpha-induced time course-dependent NF-kappaB activity. J. Proteome Res., 2010, 9: 3465-3478

[93.] MatitauAE, ScheidMP. Phosphorylation of MEKK3 at threonine 294 promotes 14-3-3 association to inhibit nuclear factor kappa B activation. J. Biol. Chem., 2008, 283: 13261-13268

[94.] LiuCJ. Progranulin: a promising therapeutic target for rheumatoid arthritis. FEBS Lett., 2011, 585: 3675-3680

[95.] LiuCJ, BoschX. Progranulin: a growth factor, a novel TNFR ligand, and a drug target. Pharmacol. Ther., 2012, 133: 124-132

[96.] CuiY, HettinghouseA, LiuCJ. Progranulin: a conductor of receptors orchestra, a chaperone of lysosomal enzymes and a therapeutic target for multiple diseases. Cytokine Growth Factor Rev., 2019, 45: 53-64

[97.] Jian, J., Konopka, J. & Liu, C. Insights into the role of progranulin in immunity, infection, and inflammation. J. Leukoc. Biol.93, 199–208 (2012).

[98.] Jian, J., Li, G., Hettinghouse, A. & Liu, C. Progranulin: a key player in autoimmune diseases. Cytokine101, 48–55 (2016).

[99.] HuangG, JianJ, LiuCJ. Progranulinopathy: a diverse realm of disorders linked to progranulin imbalances. Cytokine Growth Factor Rev., 2024, 76: 142-159

[100.] FuW, HettinghouseA, LiuCJ. In vitro, physical and functional interaction assays to examine the binding of progranulin derivative atsttrin to TNFR2 and its anti-TNFalpha activity. Methods Mol. Biol., 2021, 2248: 109-119

[101.] MoradiL, et al. . Injectable hydrogel for sustained delivery of progranulin derivative Atsttrin in treating diabetic fracture healing. Biomaterials, 2023, 301

[102.] WeiJL, et al. . Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models. Arthritis Res. Ther., 2017, 19: 280

[103.] ZhaoYP, TianQY, LiuCJ. Progranulin deficiency exaggerates, whereas progranulin-derived Atsttrin attenuates, severity of dermatitis in mice. FEBS Lett., 2013, 587: 1805-1810

[104.] HettinghouseA, FuW, LiuCJ. Monitoring atsttrin-mediated inhibition of TNFalpha/NF-kappabeta activation through in vivo bioluminescence imaging. Methods Mol. Biol., 2021, 2248: 201-210

[105.] KatyalP, et al. . Injectable recombinant block polymer gel for sustained delivery of therapeutic protein in post traumatic osteoarthritis. Biomaterials, 2022, 281

[106.] ZhaoYP, et al. . Progranulin protects against osteoarthritis through interacting with TNF-alpha and beta-Catenin signalling. Ann. Rheum. Dis., 2015, 74: 2244-2253

[107.] AguileraC, et al. . Efficient nuclear export of p65-IkappaBalpha complexes requires 14-3-3 proteins. J. Cell Sci., 2006, 119: 3695-3704

[108.] Ingles-EsteveJ, et al. . Inhibition of specific NF-kappaB activity contributes to the tumor suppressor function of 14-3-3sigma in breast cancer. PloS One, 2012, 7: e38347

[109.] HartmanAM, HirschAKH. Molecular insight into specific 14-3-3 modulators: Inhibitors and stabilisers of protein-protein interactions of 14-3-3. Eur. J. Med. Chem., 2017, 136: 573-584

[110.] MoriM, VignaroliG, BottaM. Small molecules modulation of 14-3-3 protein-protein interactions. Drug Discov. Today Technol., 2013, 10: e541-547

[111.] ZhaoJ, MeyerkordCL, DuY, KhuriFR, FuH. 14-3-3 proteins as potential therapeutic targets. Semin. Cell Dev. Biol., 2011, 22: 705-712

[112.] MilroyLG, BrunsveldL, OttmannC. Stabilization and inhibition of protein-protein interactions: the 14-3-3 case study. ACS Chem. Biol., 2013, 8: 27-35

[113.] TianQ, HeXC, HoodL, LiL. Bridging the BMP and Wnt pathways by PI3 kinase/Akt and 14-3-3zeta. Cell Cycle, 2005, 4: 215-216

[114.] BatraN, RiquelmeMA, BurraS, JiangJX. 14-3-3theta facilitates plasma membrane delivery and function of mechanosensitive connexin 43 hemichannels. J. Cell Sci., 2014, 127: 137-146

[115.] BroniszA, et al. . Microphthalmia-associated transcription factor interactions with 14-3-3 modulate differentiation of committed myeloid precursors. Mol. Biol. Cell, 2006, 17: 3897-3906

[116.] AldanaAA, UhartM, AbrahamGA, BustosDM, BoccacciniAR. 14-3-3epsilon protein-loaded 3D hydrogels favor osteogenesis. J. Mater. Sci. Mater. Med., 2020, 31: 105

[117.] LiuY, RossJF, BodinePV, BilliardJ. Homodimerization of Ror2 tyrosine kinase receptor induces 14-3-3(beta) phosphorylation and promotes osteoblast differentiation and bone formation. Mol. Endocrinol., 2007, 21: 3050-3061

[118.] KongD, et al. . Procoxacin bidirectionally inhibits osteoblastic and osteoclastic activity in bone and suppresses bone metastasis of prostate cancer. J. Exp. Clin. Cancer Res., 2023, 42: 45

[119.] SchwarzT, MurphyS, SohnC, ManskyKC. C-TAK1 interacts with microphthalmia-associated transcription factor, MITF, but not the related family member Tfe3. Biochem. Biophys. Res. Commun., 2010, 394: 890-895

[120.] van Beers-TasMH, MarottaA, BoersM, MaksymowychWP, van SchaardenburgD. A prospective cohort study of 14-3-3eta in ACPA and/or RF-positive patients with arthralgia. Arthritis Res. Ther., 2016, 18: 76

[121.] GrozingerCM, SchreiberSL. Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization. Proc. Natl. Acad. Sci., 2000, 97: 7835-7840

[122.] MiskaEA, et al. . Differential localization of HDAC4 orchestrates muscle differentiation. Nucleic Acids Res., 2001, 29: 3439-3447

[123.] GuanY, et al. . Subcellular relocation of histone deacetylase 4 regulates growth plate chondrocyte differentiation through Ca²⁺/calmodulin-dependent kinase IV. Am. J. Physiol. Cell Physiol., 2012, 303: C33-40

[124.] Frontini-LopezYR, GojanovichAD, Del VelizS, UhartM, BustosDM. 14-3-3beta isoform is specifically acetylated at Lys51 during differentiation to the osteogenic lineage. J. Cell. Biochem., 2021, 122: 1767-1780

[125.] NishimoriS, WeinMN, KronenbergHM. PTHrP targets salt-inducible kinases, HDAC4 and HDAC5, to repress chondrocyte hypertrophy in the growth plate. Bone, 2021, 142

[126.] PandeyA, BhutaniN. Profiling joint tissues at single-cell resolution: advances and insights. Nat. Rev. Rheumatol., 2024, 20: 7-20

[127.] Kadiri, M. et al. 14-3-3eta Promotes invadosome formation via the FOXO3-snail axis in rheumatoid arthritis fibroblast-like synoviocytes. Int. J. Mol. Sci.23, 123 (2021).

[128.] BarryEF, et al. . 14-3-3:Shc scaffolds integrate phosphoserine and phosphotyrosine signaling to regulate phosphatidylinositol 3-kinase activation and cell survival. J. Biol. Chem., 2009, 284: 12080-12090

[129.] JiangJ, et al. . 14-3-3 regulates the LNK/JAK2 pathway in mouse hematopoietic stem and progenitor cells. J. Clin. Investig., 2012, 122: 2079-2091

[130.] ZhaoR, et al. . MiR-204/14-3-3zeta axis regulates osteosarcoma cell proliferation through SATA3 pathway. Die Pharm., 2017, 72: 593-598

[131.] ChoiEY, et al. . Regulation of LFA-1-dependent inflammatory cell recruitment by Cbl-b and 14-3-3 proteins. Blood, 2008, 111: 3607-3614

[132.] ZhouRP, et al. . Modulators of ASIC1a and its potential as a therapeutic target for age-related diseases. Ageing Res. Rev., 2023, 83

[133.] LaiY, et al. . ADAMTS-7 forms a positive feedback loop with TNF-alpha in the pathogenesis of osteoarthritis. Ann. Rheum. Dis., 2014, 73: 1575-1584

[134.] Lin, E. A. & Liu, C. J. The emerging roles of ADAMTS-7 and ADAMTS-12 matrix metalloproteinases. Open Acess Rheumatol.1,121–131 (2009).

[135.] LinEA, LiuCJ. The role of ADAMTSs in arthritis. Protein Cell, 2010, 1: 33-47

[136.] LeeSW, et al. . A purified extract from clematis mandshurica prevents staurosporin-induced downregulation of 14-3-3 and subsequent apoptosis on rat chondrocytes. J. Ethnopharmacol., 2007, 111: 213-218

[137.] YaoQ, et al. . Osteoarthritis: pathogenic signaling pathways and therapeutic targets. Signal Transduct. Target Ther., 2023, 8: 56

[138.] ChijimatsuR, SaitoT. Mechanisms of synovial joint and articular cartilage development. Cell Mol. Life Sci., 2019, 76: 3939-3952

[139.] DengZH, LiYS, GaoX, LeiGH, HuardJ. Bone morphogenetic proteins for articular cartilage regeneration. Osteoarthr. Cartil., 2018, 26: 1153-1161

[140.] YinB, et al. . Harnessing tissue-derived extracellular vesicles for osteoarthritis theranostics. Theranostics, 2022, 12: 207-231

[141.] GardinoAK, YaffeMB. 14-3-3 proteins as signaling integration points for cell cycle control and apoptosis. Semin Cell Dev. Biol., 2011, 22: 688-695

[142.] TanY, RuanH, DemeterMR, CombMJ. p90(RSK) blocks bad-mediated cell death via a protein kinase C-dependent pathway. J. Biol. Chem., 1999, 274: 34859-34867

[143.] PriamS, et al. . Identification of soluble 14-3-3∊ as a novel subchondral bone mediator involved in cartilage degradation in osteoarthritis. Arthritis Rheum., 2013, 65: 1831-1842

[144.] NeflaM, et al. . The pro-inflammatory cytokine 14-3-3epsilon is a ligand of CD13 in cartilage. J. Cell Sci., 2015, 128: 3250-3262

[145.] GhaffariA, LiY, KilaniRT, GhaharyA. 14-3-3 sigma associates with cell surface aminopeptidase N in the regulation of matrix metalloproteinase-1. J. Cell Sci., 2010, 123: 2996-3005

[146.] AliSA, et al. . Circulating microRNAs differentiate fast-progressing from slow-progressing and non-progressing knee osteoarthritis in the osteoarthritis initiative cohort. Ther. Adv. Musculoskelet. Dis., 2022, 14

[147.] HulmeCH, et al. . Identification of candidate synovial fluid biomarkers for the prediction of patient outcome after microfracture or osteotomy. Am. J. Sports Med., 2021, 49: 1512-1523

[148.] Rockel, J. S. & Kapoor, M. The metabolome and osteoarthritis: possible contributions to symptoms and pathology. Metabolites8, 92 (2018).

[149.] HuangJ, et al. . Association between higher triglyceride glucose index and increased risk of osteoarthritis: data from NHANES 2015-2020. BMC Public Health, 2024, 24

[150.] ChibaD, et al. . Higher fasting blood glucose worsens knee symptoms in patients with radiographic knee osteoarthritis and comorbid central sensitization: an Iwaki cohort study. Arthritis Res. Ther., 2022, 24: 269

[151.] JiL, et al. . The 14-3-3 protein YWHAB inhibits glucagon-induced hepatic gluconeogenesis through interacting with the glucagon receptor and FOXO1. FEBS Lett., 2021, 595: 1275-1288

[152.] NeumannJ, et al. . Type 2 diabetes patients have accelerated cartilage matrix degeneration compared to diabetes free controls: data from the Osteoarthritis Initiative. Osteoarthr. Cartil., 2018, 26: 751-761

[153.] ThandavarayanRA, et al. . 14-3-3 protein regulates Ask1 signaling and protects against diabetic cardiomyopathy. Biochem. Pharmacol., 2008, 75: 1797-1806

[154.] LimGE, et al. . 14-3-3zeta coordinates adipogenesis of visceral fat. Nat. Commun., 2015, 6

[155.] WilliamsA, WangEC, ThurnerL, LiuCJ. Review: novel insights into tumor necrosis factor receptor, death receptor 3, and progranulin pathways in arthritis and bone remodeling. Arthritis Rheumatol., 2016, 68: 2845-2856

[156.] XuY, ChenF. Acid-sensing ion channel-1a in articular chondrocytes and synovial fibroblasts: a novel therapeutic target for rheumatoid arthritis. Front. Immunol., 2020, 11

[157.] GravalleseEM, FiresteinGS. Rheumatoid arthritis - common origins, divergent mechanisms. N. Engl. J. Med., 2023, 388: 529-542

[158.] ZengT, TanL, WuY, YuJ. 14-3-3eta protein in rheumatoid arthritis: promising diagnostic marker and independent risk factor for osteoporosis. Lab. Med., 2020, 51: 529-539

[159.] HammamN, SalahS, KholefEF, MoussaEM, MarottaA. 14-3-3eta protein in serum and synovial fluid correlates with radiographic damage and progression in a longitudinal evaluation of patients with established rheumatoid arthritis. Mod. Rheumatol., 2020, 30: 664-670

[160.] HirataS, MarottaA, GuiY, HanamiK, TanakaY. Serum 14-3-3eta level is associated with severity and clinical outcomes of rheumatoid arthritis, and its pretreatment level is predictive of DAS28 remission with tocilizumab. Arthritis Res. Ther., 2015, 17: 280

[161.] MaksymowychWP, et al. . Serum 14-3-3eta is a novel marker that complements current serological measurements to enhance detection of patients with rheumatoid arthritis. J. Rheumatol., 2014, 41: 2104-2113

[162.] ZhangY, et al. . ASIC1a induces synovial inflammation via the Ca²⁺/NFATc3/ RANTES pathway. Theranostics, 2020, 10: 247-264

[163.] XuY, et al. . Acid sensor ASIC1a induces synovial fibroblast proliferation via Wnt/beta-catenin/c-Myc pathway in rheumatoid arthritis. Int. Immunopharmacol., 2022, 113

[164.] NiuR, et al. . ASIC1a promotes synovial invasion of rheumatoid arthritis via Ca²⁺/Rac1 pathway. Int. Immunopharmacol., 2020, 79

[165.] WeiF, et al. . PGRN protects against colitis progression in mice in an IL-10 and TNFR2 dependent manner. Sci. Rep., 2014, 4

[166.] WeiJL, BuzaJ3rd, LiuCJ. Does progranulin account for the opposite effects of etanercept and infliximab/adalimumab in osteoarthritis? Comment on Olson et al.: “Therapeutic opportunities to prevent post-traumatic arthritis: lessons from the natural history of arthritis after articular fracture”. J. Orthop. Res., 2016, 34: 12-14

[167.] KilaniRT, et al. . Detection of high levels of 2 specific isoforms of 14-3-3 proteins in synovial fluid from patients with joint inflammation. J. Rheumatol., 2007, 34: 1650-1657

[168.] HuangY, YangM, HuangW. 14-3-3 sigma: a potential biomolecule for cancer therapy. Clin. Chim. Acta. Int. J. Clin. Chem., 2020, 511: 50-58

[169.] MeltzerPS, HelmanLJ. New horizons in the treatment of osteosarcoma. N. Engl. J. Med., 2021, 385: 2066-2076

[170.] GorlickR, et al. . Children’s Oncology group’s 2013 blueprint for research: bone tumors. Pediatr. Blood Cancer, 2013, 60: 1009-1015

[171.] KagerL, et al. . Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J. Clin. Oncol., 2003, 21: 2011-2018

[172.] YangZ, et al. . 14-3-3sigma downregulation suppresses ICC metastasis via impairing migration, invasion, and anoikis resistance of ICC cells. Cancer Biomark., 2017, 19: 313-325

[173.] XiaoY, et al. . 14-3-3tau promotes breast cancer invasion and metastasis by inhibiting RhoGDIalpha. Mol. Cell Biol., 2014, 34: 2635-2649

[174.] HaoX, et al. . CircPAK1 promotes the progression of hepatocellular carcinoma via modulation of YAP nucleus localization by interacting with 14-3-3zeta. J. Exp. Clin. Cancer Res., 2022, 41: 281

[175.] ChuYW, WangCR, WengFB, YanZJ, WangC. MicroRNA-222 contributed to cell proliferation, invasion and migration via regulating YWHAG in osteosarcoma. Eur. Rev. Med. Pharm. Sci., 2018, 22: 2588-2597

[176.] KimKO, et al. . Proteomic identification of 14-3-3ϵ as a linker protein between pERK1/2 inhibition and BIM upregulation in human osteosarcoma cells. J. Orthop. Res., 2014, 32: 848-854

[177.] AhrensWA, RidenourRV3rd, CaronBL, MillerDV, FolpeAL. GLUT-1 expression in mesenchymal tumors: an immunohistochemical study of 247 soft tissue and bone neoplasms. Hum. Pathol., 2008, 39: 1519-1526

[178.] NgoS, BarryJB, NisbetJC, PrinsJB, WhiteheadJP. Reduced phosphorylation of AS160 contributes to glucocorticoid-mediated inhibition of glucose uptake in human and murine adipocytes. Mol. Cell. Endocrinol., 2009, 302: 33-40

[179.] ShanHJ, GuWX, DuanG, ChenHL. Fat mass and obesity-associated (FTO)-mediated N6-methyladenosine modification of Kruppel-like factor 3 (KLF3) promotes osteosarcoma progression. Bioengineered, 2022, 13: 8038-8050

[180.] Bereza, M. et al. Epigenetic abnormalities in chondrosarcoma. Int. J. Mol. Sci.24, 4539 (2023).

[181.] RockA, AliS, ChowWA. Systemic therapy for chondrosarcoma. Curr. Treat. Options Oncol., 2022, 23: 199-209

[182.] GiuffridaAY, et al. . Chondrosarcoma in the United States (1973 to 2003): an analysis of 2890 cases from the SEER database. J. Bone Jt. Surg. Am., 2009, 91: 1063-1072

[183.] Evans, H. L., Ayala, A. G. & Romsdahl, M. M. Prognostic factors in chondrosarcoma of bone: a clinicopathologic analysis with emphasis on histologic grading. Cancer40, 818–831 (1977).

[184.] GelderblomH, et al. . The clinical approach towards chondrosarcoma. Oncologist, 2008, 13: 320-329

[185.] WhelanJS, DavisLE. Osteosarcoma, chondrosarcoma, and chordoma. J. Clin. Oncol., 2018, 36: 188-193

[186.] YangWH, et al. . Epigallocatechin-3-gallate induces cell apoptosis of human chondrosarcoma cells through apoptosis signal-regulating kinase 1 pathway. J. Cell Biochem., 2011, 112: 1601-1611

[187.] KiddME, ShumakerDK, RidgeKM. The role of vimentin intermediate filaments in the progression of lung cancer. Am. J. Respir. Cell Mol. Biol., 2014, 50: 1-6

[188.] WuYJ, JanYJ, KoBS, LiangSM, LiouJY. Involvement of 14-3-3 proteins in regulating tumor progression of hepatocellular carcinoma. Cancers, 2015, 7: 1022-1036

[189.] LeeJXT, et al. . YWHAG deficiency disrupts the EMT-associated network to induce oxidative cell death and prevent metastasis. Adv. Sci., 2023, 10

[190.] ShinoharaN, et al. . TGF-beta signalling and PEG10 are mutually exclusive and inhibitory in chondrosarcoma cells. Sci. Rep., 2017, 7

[191.] HongHY, JeonWK, KimSJ, KimBC. 14-3-3 sigma is a new target up-regulated by transforming growth factor-beta1 through a Smad3-dependent mechanism. Biochem. Biophys. Res. Commun., 2013, 432: 193-197

[192.] XuJ, et al. . 14-3-3zeta turns TGF-beta’s function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2. Cancer Cell, 2015, 27: 177-192

[193.] LiG, et al. . Slug signaling is up-regulated by CCL21/CCR7 [corrected] to induce EMT in human chondrosarcoma. Med. Oncol., 2015, 32

[194.] HuangXY, et al. . alphaB-crystallin complexes with 14-3-3zeta to induce epithelial-mesenchymal transition and resistance to sorafenib in hepatocellular carcinoma. Hepatology, 2013, 57: 2235-2247

[195.] RaychaudhuriK, et al. . 14-3-3sigma gene loss leads to activation of the epithelial to mesenchymal transition due to the stabilization of c-jun protein. J. Biol. Chem., 2016, 291: 16068-16081

[196.] CowanAJ, et al. . Diagnosis and management of multiple myeloma: a review. JAMA, 2022, 327: 464-477

[197.] CowanAJ, et al. . Global burden of multiple myeloma: a systematic analysis for the global burden of disease study 2016. JAMA Oncol., 2018, 4: 1221-1227

[198.] SiegelRL, MillerKD, JemalA. Cancer statistics, 2020. CA Cancer J. Clin., 2020, 70: 7-30

[199.] MinnieSA, HillGR. Immunotherapy of multiple myeloma. J. Clin. Investig., 2020, 130: 1565-1575

[200.] Diaz de la GuardiaR, et al. . Expression profile of telomere-associated genes in multiple myeloma. J. Cell Mol. Med., 2012, 16: 3009-3021

[201.] ObengEA, et al. . Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood, 2006, 107: 4907-4916

[202.] BianchiG, et al. . The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition. Blood, 2009, 113: 3040-3049

[203.] GuY, et al. . 14-3-3zeta binds the proteasome, limits proteolytic function, and enhances sensitivity to proteasome inhibitors. Leukemia, 2018, 32: 744-751

[204.] TakahashiT, et al. . Synergistic combination therapy with cotylenin A and vincristine in multiple myeloma models. Int. J. Oncol., 2015, 46: 1801-1809

[205.] DehlinM, JacobssonL, RoddyE. Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors. Nat. Rev. Rheumatol., 2020, 16: 380-390

[206.] WijnandsJM, et al. . Determinants of the prevalence of gout in the general population: a systematic review and meta-regression. Eur. J. Epidemiol., 2015, 30: 19-33

[207.] DoganI, et al. . 14-3-3 eta ETA protein as a potential marker of joint damage in gout. Clin. Biochem., 2023, 118

[208.] Phipps-GreenAJ, et al. . Twenty-eight loci that influence serum urate levels: analysis of association with gout. Ann. Rheum. Dis., 2016, 75: 124-130

[209.] MartinonF, GlimcherLH. Gout: new insights into an old disease. J. Clin. Investig., 2006, 116: 2073-2075

[210.] van de VeerdonkFL, NeteaMG, DinarelloCA, JoostenLA. Inflammasome activation and IL-1beta and IL-18 processing during infection. Trends Immunol., 2011, 32: 110-116

[211.] TranTH, PhamJT, ShafeeqH, ManigaultKR, AryaV. Role of interleukin-1 inhibitors in the management of gout. Pharmacotherapy, 2013, 33: 744-753

[212.] LiuYR, WangJQ, LiJ. Role of NLRP3 in the pathogenesis and treatment of gout arthritis. Front. Immunol., 2023, 14

[213.] ReidIR, BillingtonEO. Drug therapy for osteoporosis in older adults. Lancet, 2022, 399: 1080-1092

[214.] JohnstonCB, DagarM. Osteoporosis in older adults. Med. Clin. North Am., 2020, 104: 873-884

[215.] JohnellO, KanisJA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos. Int., 2006, 17: 1726-1733

[216.] KanisJA, et al. . Long-term risk of osteoporotic fracture in Malmo. Osteoporos. Int., 2000, 11: 669-674

[217.] JiangHX, et al. . Development and initial validation of a risk score for predicting in-hospital and 1-year mortality in patients with hip fractures. J. Bone Min. Res., 2005, 20: 494-500

[218.] VilacaT, EastellR, SchiniM. Osteoporosis in men. Lancet Diabetes Endocrinol., 2022, 10: 273-283

[219.] AnishRJ, NairA. Osteoporosis management-current and future perspectives—a systemic review. J. Orthop., 2024, 53: 101-113

[220.] HuangJ, HuangJ, HuW, ZhangZ. Heat shock protein 90 alpha and 14-3-3eta in postmenopausal osteoporotic rats with varying levels of serum FSH. Climacteric, 2020, 23: 581-590

[221.] AbdelhafizD, BakerT, GlascowDA, AbdelhafizA. Biomarkers for the diagnosis and treatment of rheumatoid arthritis—a systematic review. Postgrad. Med., 2023, 135: 214-223

[222.] TaoH, et al. . Urolithin A suppresses RANKL-induced osteoclastogenesis and postmenopausal osteoporosis by, suppresses inflammation and downstream NF-kappaB-activated pyroptosis pathways. Pharm. Res., 2021, 174

[223.] AnY, et al. . Activation of ROS/MAPKs/NF-kappaB/NLRP3 and inhibition of efferocytosis in osteoclast-mediated diabetic osteoporosis. FASEB J., 2019, 33: 12515-12527

[224.] LiY, et al. . Urolithin B suppressed osteoclast activation and reduced bone loss of osteoporosis via inhibiting ERK/NF-kappaB pathway. Cell Prolif., 2022, 55

[225.] LiS, et al. . 14-3-3 protein of neospora caninum modulates host cell innate immunity through the activation of MAPK and NF-kappaB pathways. Front. Microbiol., 2019, 10: 37

[226.] YangT, et al. . RDIVpSGP motif of ASPP2 binds to 14-3-3 and enhances ASPP2/k18/14-3-3 ternary complex formulation to promote BRAF/MEK/ERK signal-inhibited cell proliferation in hepatocellular carcinoma. Cancer Gene Ther., 2022, 29: 1616-1627

[227.] OttmannC, et al. . A structural rationale for selective stabilization of anti-tumor interactions of 14-3-3 proteins by cotylenin A. J. Mol. Biol., 2009, 386: 913-919

[228.] AndersC, et al. . A semisynthetic fusicoccane stabilizes a protein-protein interaction and enhances the expression of K⁺ channels at the cell surface. Chem. Biol., 2013, 20: 583-593

[229.] BierD, et al. . Small-molecule stabilization of the 14-3-3/Gab2 protein-protein interaction (PPI) interface. Chem. Med. Chem., 2016, 11: 911-918

[230.] RoseR, et al. . Identification and structure of small-molecule stabilizers of 14-3-3 protein-protein interactions. Angew. Chem. Int. Ed. Engl., 2010, 49: 4129-4132

[231.] RichterA, RoseR, HedbergC, WaldmannH, OttmannC. An optimised small-molecule stabiliser of the 14-3-3-PMA2 protein-protein interaction. Chemistry, 2012, 18: 6520-6527

[232.] SatoS, et al. . Metabolite regulation of nuclear localization of carbohydrate-response element-binding protein (ChREBP): role of AMP as an allosteric inhibitor. J. Biol. Chem., 2016, 291: 10515-10527

[233.] TakahashiS, WakuiH, GustafssonJA, ZilliacusJ, ItohH. Functional interaction of the immunosuppressant mizoribine with the 14-3-3 protein. Biochem. Biophys. Res. Commun., 2000, 274: 87-92

[234.] ManciniM, et al. . A new nonpeptidic inhibitor of 14-3-3 induces apoptotic cell death in chronic myeloid leukemia sensitive or resistant to imatinib. J. Pharm. Exp. Ther., 2011, 336: 596-604

[235.] ZhaoJ, et al. . Discovery and structural characterization of a small molecule 14-3-3 protein-protein interaction inhibitor. Proc. Natl. Acad. Sci. USA, 2011, 108: 16212-16216

[236.] OttmannC, et al. . Structure of a 14-3-3 coordinated hexamer of the plant plasma membrane H⁺ -ATPase by combining X-ray crystallography and electron cryomicroscopy. Mol. Cell, 2007, 25: 427-440

[237.] WuH, GeJ, YaoSQ. Microarray-assisted high-throughput identification of a cell-permeable small-molecule binder of 14-3-3 proteins. Angew. Chem. Int. Ed. Engl., 2010, 49: 6528-6532

[238.] AghazadehY, PapadopoulosV. The role of the 14-3-3 protein family in health, disease, and drug development. Drug Discov. Today, 2016, 21: 278-287

[239.] ArrendaleA, et al. . Synthesis of a phosphoserine mimetic prodrug with potent 14-3-3 protein inhibitory activity. Chem. Biol., 2012, 19: 764-771

[240.] CorradiV, et al. . Computational techniques are valuable tools for the discovery of protein-protein interaction inhibitors: the 14-3-3σ case. Bioorg. Med. Chem. Lett., 2011, 21: 6867-6871

[241.] MoriM, et al. . Discovery of 14-3-3 protein-protein interaction inhibitors that sensitize multidrug-resistant cancer cells to doxorubicin and the Akt inhibitor GSK690693. Chem. Med. Chem., 2014, 9: 973-983

[242.] ParkKD, et al. . Identification of a lacosamide binding protein using an affinity bait and chemical reporter strategy: 14-3-3 ζ. J. Am. Chem. Soc., 2011, 133: 11320-11330

[243.] OttmannC. Small-molecule modulators of 14-3-3 protein-protein interactions. Bioorg. Med. Chem., 2013, 21: 4058-4062

[244.] SawadaM, et al. . Synthesis and anti-migrative evaluation of moverastin derivatives. Bioorg. Med. Chem. Lett., 2011, 21: 1385-1389

[245.] DuY, MastersSC, KhuriFR, FuH. Monitoring 14-3-3 protein interactions with a homogeneous fluorescence polarization assay. J. Biomol. Screen, 2006, 11: 269-276

[246.] BierD, et al. . Molecular tweezers modulate 14-3-3 protein-protein interactions. Nat. Chem., 2013, 5: 234-239

[247.] MastersSC, FuH. 14-3-3 proteins mediate an essential anti-apoptotic signal. J. Biol. Chem., 2001, 276: 45193-45200

[248.] AghazadehY, Martinez-ArguellesDB, FanJ, CultyM, PapadopoulosV. Induction of androgen formation in the male by a TAT-VDAC1 fusion peptide blocking 14-3-3ɛ protein adaptor and mitochondrial VDAC1 interactions. Mol. Ther., 2014, 22: 1779-1791

[249.] XuY, et al. . YWHAE/14-3-3epsilon expression impacts the protein load, contributing to proteasome inhibitor sensitivity in multiple myeloma. Blood, 2020, 136: 468-479

Funding

U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)(R01NS070328); U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)