Affinage

CD74

HLA class II histocompatibility antigen gamma chain · UniProt P04233

Length
296 aa
Mass
33.5 kDa
Annotated
2026-06-09
100 papers in source corpus 36 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD74 is a type II transmembrane protein that serves as the principal cell-surface receptor for the cytokine MIF (and the structurally related ligands MIF-2 and TIMP-1), transducing extracellular signals into proliferative, survival, migratory, and immune-modulatory programs across diverse cell types (PMID:19665027, PMID:24760155, PMID:37508563). Productive signaling requires CD74 to assemble into heteromeric receptor complexes, most prominently with CXCR4, which co-immunoprecipitates with CD74 from monocytes and is required for MIF-stimulated AKT activation, endosomal trafficking of internalized ligand, ZAP-70 activation, and chemotaxis (PMID:19665027, PMID:22014447, PMID:24760155, PMID:38992165). Ligand engagement drives a recurring set of downstream cascades — PI3K/AKT, ERK1/2, p38, and NF-κB — whose outputs are context-dependent: in B cells and epithelial/tumor cells they promote survival and proliferation through NF-κB-driven TAp63/BCL-2 and BCL-XL induction (PMID:16484589, PMID:17846227, PMID:20614481), whereas soluble CD74 can reroute MIF signaling toward RIP1/RIP3 necroptosis (PMID:30371153). Beyond surface signaling, MIF binding triggers intramembrane cleavage that liberates the CD74 intracellular domain (CD74-ICD), which translocates to the nucleus and functions as a transcriptional regulator: it partners with RUNX and NF-κB on apoptosis, immune, and migration genes in CLL B cells, forms a cytosolic complex with PAX5 to repress the tumor suppressor DMTF1, and directs SP1-mediated IL-1β repression in dendritic cells (PMID:28031488, PMID:36323260, PMID:39576827). CD74 also acts as a transcription factor in its own right in polycystic kidney disease, binding fibrotic gene and MIF promoters to establish a feed-forward inflammatory loop (PMID:38534333). Through these activities CD74 governs B-cell and HSC homeostasis, regulatory T-cell tumor infiltration, macrophage polarization and phagocytosis, osteoclastogenesis, and intestinal epithelial repair (PMID:24760155, PMID:23044992, PMID:32004754, PMID:33661886, PMID:38702311, PMID:39111632). A recurrent CD74-NRG1 gene fusion exploits the CD74 transmembrane anchor to display the NRG1 EGF-like domain extracellularly, driving ERBB2:ERBB3 heterodimerization and oncogenic transformation (PMID:24469108, PMID:35247925). CD74 protein levels are set in part by lysosomal degradation (PMID:22042694).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2006 Medium

    Established that CD74 is not merely an MHC class II chaperone but an active surface receptor whose engagement drives B-cell proliferation and survival.

    Evidence Anti-CD74 antibody stimulation of B cells with NF-κB reporter, BrdU, and BCL-XL readouts

    PMID:16484589

    Open questions at the time
    • Identity of the physiological ligand not addressed in this study
    • Receptor partners mediating signaling not yet defined
  2. 2007 Medium

    Defined the pathway order downstream of CD74, showing NF-κB induces TAp63 which transactivates BCL-2 to confer the antiapoptotic effect.

    Evidence CD74 stimulation in primary B cells with ChIP for TAp63 at the BCL-2 promoter and apoptosis assays

    PMID:17846227

    Open questions at the time
    • Generalizability of the TAp63 axis beyond B cells unknown
    • Direct CD74-to-NF-κB coupling mechanism not resolved
  3. 2009 High

    Resolved how CD74 transduces signal despite a short cytoplasmic tail by demonstrating a functional CD74/CXCR4 heteromeric receptor complex.

    Evidence Reciprocal Co-IP from primary monocytes plus AMD3100/antibody blockade of MIF-induced AKT in transfected cells

    PMID:19665027

    Open questions at the time
    • Stoichiometry and structural architecture of the complex not determined
    • Whether all CD74 signaling requires CXCR4 not established
  4. 2011 High

    Showed MIF/CD74/CXCR4 signaling occurs from endosomes following clathrin/dynamin-dependent internalization, linking receptor trafficking to signal output.

    Evidence Endocytosis inhibitors, CD74 overexpression, CXCR4 blockade, endosomal colocalization, and AKT readout in HEK293/HeLa

    PMID:22014447

    Open questions at the time
    • Adaptor proteins linking CD74 to clathrin machinery unidentified
    • Fate of internalized receptor (recycling vs degradation) not traced here
  5. 2014 High

    Demonstrated CD74/CXCR4 cooperatively drive MIF-induced chemotaxis via ZAP-70, defining a migratory effector arm.

    Evidence Cd74-/- and ZAP-70-/- mouse B cells, Transwell migration, Ca2+ and F-actin assays, siRNA in Ramos cells

    PMID:24760155

    Open questions at the time
    • Mechanism coupling CD74 to ZAP-70 activation unknown
    • Whether other cell types use this ZAP-70 route untested
  6. 2014 Medium

    Mapped the MIF-binding region on CD74 by showing HLA-DRα1 competitively blocks MIF binding and an L50Q mutation enhances blockade.

    Evidence MIF-CD74 binding competition assay, EAE model, pERK1/2 readout, and mutagenesis

    PMID:24683185 PMID:30353480

    Open questions at the time
    • No high-resolution structure of the MIF-CD74 interface
    • Affinity quantification limited
  7. 2016 High

    Discovered that the cleaved CD74-ICD acts as a nuclear transcriptional regulator, connecting surface engagement to gene-expression control in CLL.

    Evidence ChIP-seq for CD74-ICD binding plus Co-IP with RUNX and NF-κB in CLL cells

    PMID:28031488

    Open questions at the time
    • Protease performing intramembrane cleavage not identified
    • Mechanism of ICD nuclear import unresolved
  8. 2022 High

    Identified a CD74-ICD:PAX5 complex repressing the tumor suppressor DMTF1 in normal B cells, a function lost in CLL, extending the transcriptional role of the ICD.

    Evidence Co-IP of CD74-ICD with PAX5 and ChIP at the DMTF1 promoter in normal vs CLL B cells

    PMID:36323260

    Open questions at the time
    • How CLL disrupts this repression mechanistically unclear
    • Direct DNA contact vs PAX5-tethered binding not distinguished
  9. 2024 High

    Expanded CD74-ICD transcriptional control to dendritic cells, where it induces SP1 to repress IL-1β and promote tolerogenic immunity in breast cancer.

    Evidence Cell-type-specific conditional KO, ChIP for CD74-ICD at the SP1 promoter, and tol-DC/Breg profiling

    PMID:39576827

    Open questions at the time
    • Direct ICD-SP1 promoter binding vs co-factor recruitment not fully separated
    • Translation to human tumors not shown
  10. 2024 High

    Showed CD74 itself binds gene promoters as a transcription factor in ADPKD, upregulating fibrotic genes and MIF in a feed-forward loop.

    Evidence CD74-KO in Pkd1 mutant mice with ChIP at fibrotic and MIF promoters and pathway Western blots

    PMID:38534333

    Open questions at the time
    • Whether full-length CD74 or ICD mediates promoter binding ambiguous
    • Direct DNA-binding domain not mapped
  11. 2014 High

    Established the CD74-NRG1 fusion as an oncogenic driver that displays the NRG1 EGF-like domain to activate ERBB3/PI3K-AKT.

    Evidence Transcriptome sequencing, ectopic expression in lung cancer lines, phospho-ERBB3/AKT, and soft-agar assays

    PMID:24469108

    Open questions at the time
    • In vivo tumorigenicity not yet shown at this stage
    • Whether endogenous CD74 functions feed into fusion signaling unknown
  12. 2022 High

    Confirmed CD74-NRG1 directly binds ERBB3 to force ERBB2:ERBB3 heterodimerization and drive ligand-independent transformation in vivo.

    Evidence CD74-NRG1 transgenic mice, ERBB3 binding assay, and NRG1-independent proliferation

    PMID:26837769 PMID:35247925

    Open questions at the time
    • Contribution of the CD74 portion beyond membrane anchoring unclear
    • Therapeutic vulnerabilities of the fusion in patients not addressed
  13. 2018 Medium

    Revealed that soluble CD74 reroutes MIF signaling from AKT survival to RIP1/RIP3 necroptosis, showing receptor solubility tunes cell-fate output.

    Evidence Recombinant sCD74/MIF co-treatment with RIP1/RIP3 inhibition and AKT/p38 readouts in cardiac fibroblasts

    PMID:30371153

    Open questions at the time
    • Source and physiological abundance of soluble CD74 unclear
    • Cell-type specificity mechanism not resolved
  14. 2023 Medium

    Broadened the CD74 ligand repertoire by showing TIMP-1 engages CD74 (sharing MIF-binding residues) to trigger internalization and AKT/ERK signaling.

    Evidence In silico docking, Co-IP, internalization, phospho-kinase array, and migration assays in monocytes

    PMID:37508563

    Open questions at the time
    • Structural interface is computational only
    • Whether TIMP-1 requires CXCR4 not established
  15. 2021 High

    Defined a homeostatic role for CD74 in restraining hematopoietic stem cell repopulation and niche competition.

    Evidence CD74-KO mice, competitive repopulation, BM transplantation, and in vitro HSPC expansion with CD74 blockade

    PMID:33661886

    Open questions at the time
    • Ligand driving HSC CD74 signaling not identified
    • Downstream effectors beyond CD18 regulation unclear
  16. 2024 High

    Showed CD74 is required for regulatory T-cell cytoskeletal organization and tumor infiltration, marking it as an immune-evasion node.

    Evidence CRISPR deletion in human primary Tregs, actin imaging, and preclinical tumor models

    PMID:38702311

    Open questions at the time
    • Molecular link from CD74 to actin cytoskeleton unresolved
    • Tumor-specific (vs steady-state) signaling trigger unknown
  17. 2024 Medium

    Showed CD74-ICD-independent surface CD74/CXCR4 complexes mediate MIF-induced T-cell migration and demonstrated chondroitin-sulfate-modified CD74 trafficking.

    Evidence Proximity ligation assay, 3D-matrix imaging, and pathway inhibitors in activated CD4+ T cells

    PMID:38992165

    Open questions at the time
    • Functional role of chondroitin sulfate modification not dissected
    • Dynamics of complex disassembly upon MIF not quantified
  18. 2024 Medium

    Implicated CD74/CXCR4 on macrophages as a phagocytosis checkpoint engaged by tumor APP via SHP-1.

    Evidence scRNA-seq cell-cell analysis, Co-IP, SHP-1 phosphorylation, and phagocytosis assays in GBM

    PMID:39111632

    Open questions at the time
    • Direct APP-CD74 binding affinity not measured
    • Whether MIF competes with APP at CD74 untested
  19. 2014 Medium

    Showed CD74 limits Fas surface availability to set apoptosis sensitivity, a function distinct from its ligand-receptor signaling.

    Evidence shRNA knockdown and in vivo full-length CD74 overexpression with Fas surface and caspase readouts

    PMID:25304249

    Open questions at the time
    • Mechanism by which CD74 retains Fas intracellularly unknown
    • Whether ICD or surface CD74 mediates the effect unclear
  20. 2011 Medium

    Linked CD74 protein abundance to lysosomal/autophagic degradation, identifying a level-setting mechanism exploitable pharmacologically.

    Evidence FTY720-induced lysosomal permeabilization with CD74, LC3-II, p62 Western blots in MCL lines

    PMID:22042694

    Open questions at the time
    • Specific lysosomal proteases acting on CD74 not identified
    • Connection to ICD generation not addressed
  21. 2022 Medium

    Assigned a protease-regulatory activity to the CD74 p41 isoform as a cathepsin L inhibitor relevant to macrophage polarization in arthritis.

    Evidence CTSL enzymatic assay, isoform qPCR, macrophage polarization, and collagen-induced arthritis model

    PMID:35245865

    Open questions at the time
    • In vivo consequences of CTSL inhibition by p41 not isolated
    • Relationship to MIF-receptor function unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of MIF/CD74 receptor assembly, the protease responsible for CD74 intramembrane cleavage, and the determinants of context-specific downstream output (survival vs death, transcriptional repression vs activation) remain unresolved.
  • No experimentally determined MIF-CD74 complex structure
  • Cleavage protease generating CD74-ICD unidentified
  • Rules governing which cell types use CXCR4, CXCR2, or CD44 co-receptors not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0140110 transcription regulator activity 4 GO:0001618 virus receptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 3 GO:0005764 lysosome 1 GO:0005768 endosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-5357801 Programmed Cell Death 2
Partners
APPCXCR4ERBB3MIFNF-KBPAX5RUNXTIMP-1
Complex memberships
CD74/CXCR4 receptor complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Cell-surface CD74 stimulation with anti-CD74 antibody triggers a signaling cascade leading to NF-κB (p65/RelA) activation, entry into S phase, DNA synthesis, cell division, and upregulation of BCL-XL, establishing CD74 as a survival receptor on B cells. Anti-CD74 antibody stimulation of B cells; NF-κB reporter assays; BrdU incorporation; flow cytometry for cell cycle; Western blot for BCL-XL Blood Medium 16484589
2007 CD74 activation by MIF/anti-CD74 induces NF-κB p65, which upregulates TAp63 expression; TAp63 then binds and transactivates the BCL-2 gene promoter, increasing BCL-2 protein and B-cell survival — defining the CD74/NF-κB/TAp63 antiapoptotic axis. CD74 stimulation in primary B cells; ChIP for TAp63 binding BCL-2 promoter; Western blot; flow cytometry for apoptosis Blood Medium 17846227
2009 CD74 forms a functional heteromeric receptor complex with CXCR4 at the cell surface; endogenous CD74/CXCR4 complexes were isolated by co-immunoprecipitation from monocytes, and MIF-stimulated AKT activation via CD74 was blocked by anti-CXCR4 antibody and AMD3100, while CXCL12-stimulated AKT was not reduced by anti-CD74. Co-immunoprecipitation from primary monocytes; CD74/CXCR4 co-expression in HEK293 cells; pharmacological blockade with AMD3100 and neutralizing antibodies; AKT phosphorylation by Western blot FEBS letters High 19665027
2011 MIF endocytosis follows a clathrin/dynamin-dependent pathway; CD74 overexpression markedly accelerates MIF internalization, CXCR4 blockade reduces it, and MIF/CD74/CXCR4 colocalize in endosomal compartments; endocytosis inhibitors reduce MIF-stimulated AKT signaling, indicating endosomal signaling. Pathway-specific endocytosis inhibitors (MDC, CPZ, dynasore, dominant-negative dynamin); CD74 overexpression in HEK293/HeLa; CXCR4 blockade with AMD3100; fluorescent MIF colocalization with endosomal markers; AKT Western blot European journal of cell biology High 22014447
2014 MIF promotes B-cell chemotaxis cooperatively through both CD74 and CXCR4; genetic deficiency of Cd74 or inhibition of CXCR4 fully abrogates MIF-induced migration; MIF stimulation activates the tyrosine kinase ZAP-70 in a CXCR4- and CD74-dependent manner, and ZAP-70 inhibition or knockdown abolishes migration. Primary murine B cells from Cd74-/- and ZAP-70-/- mice; Transwell migration assays; pharmacological inhibition of CXCR4, CD74, and ZAP-70; intracellular Ca2+ mobilization; F-actin polymerization; siRNA knockdown in Ramos cells Journal of immunology High 24760155
2014 CD74-NRG1 fusion protein leads to extracellular display of the EGF-like domain of NRG1 III-β3, providing ligand for ERBB2-ERBB3 receptor complexes; ectopic expression in lung cancer cell lines activates ERBB3 phosphorylation, PI3K-AKT pathway, and promotes soft-agar colony formation. Transcriptome sequencing; ectopic expression in lung cancer cell lines (ERBB2/3-expressing); Western blot for phospho-ERBB3 and AKT; soft-agar colony formation assay; immunohistochemistry for phospho-ERBB3 in tumor tissues Cancer discovery High 24469108
2016 Following MIF binding to CD74 and intramembrane cleavage, the released CD74 intracellular domain (CD74-ICD) acts as a transcriptional regulator in CLL B cells: it interacts with transcription factors RUNX and NF-κB and binds proximal and distal regulatory sites of genes involved in apoptosis, immune response, and cell migration. ChIP-seq for CD74-ICD binding in CLL cells; co-immunoprecipitation with RUNX and NF-κB; gene expression analysis following CD74 activation Proceedings of the National Academy of Sciences High 28031488
2022 CD74-ICD in normal B cells forms a cytosolic complex with the transcription factor PAX5; this complex binds the promoter of the tumor-suppressor gene DMTF1 and downregulates its expression through inhibition of transcription, a function that is suppressed in CLL. Co-immunoprecipitation of CD74-ICD with PAX5; ChIP for CD74-ICD:PAX5 binding at DMTF1 promoter; gene expression analysis in normal vs. CLL B cells Cell reports High 36323260
2008 CD74 functions as a MIF receptor on podocytes: MIF activates cell-surface CD74 on cultured human podocytes, leading to phosphorylation of ERK1/2 and p38; MIF-induced expression of TRAIL and MCP-1 in podocytes and tubular cells occurs in a p38-dependent manner. Western blot for phospho-ERK1/2 and phospho-p38 in cultured podocytes; flow cytometry for cell-surface CD74; ELISA for TRAIL and MCP-1; p38 inhibitor experiments Journal of the American Society of Nephrology Medium 18842989
2013 CD74 is required for MIF to inhibit osteoclastogenesis: MIF addition to WT bone marrow cultures inhibits osteoclast-like cell formation by 16%, but has no effect on CD74-KO cultures; CD74-KO mice display increased osteoclast numbers, decreased trabecular bone volume, and cortical bone loss similar to MIF-KO mice. MIF suppresses RANKL-induced NFATc1 and c-Fos protein in BMMs. Bone marrow cultures from CD74-KO and WT mice; osteoclast differentiation assay; micro-CT and histomorphometry; Western blot for NFATc1 and c-Fos Journal of bone and mineral research High 23044992
2016 MIF-CD74 signaling inhibits IFN-γ secretion in microglia through phosphorylation of ERK1/2, driving M2 polarization; siRNA-mediated or antibody-mediated inhibition of CD74 or MIF restores IFN-γ release, promotes M1 microglial polarization, and prolongs survival in glioma-implanted mice. siRNA knockdown and neutralizing antibody inhibition of CD74/MIF; Western blot for phospho-ERK1/2; IFN-γ ELISA; in vivo glioma implantation survival model Oncogene Medium 27157615
2015 IFN-γ enhances cell-surface CD74 expression on melanoma cells; CD74-MIF autocrine interaction activates PI3K/AKT (Ser473 phosphorylation), upregulates IL-6, IL-8, and BCL-2, and promotes tumor survival; blockade of CD74-MIF interaction reduces AKT phosphorylation and suppresses tumor growth in xenograft models. Western blot for phospho-AKT; flow cytometry for cell-surface CD74; neutralizing antibody blockade; xenograft mouse model; ELISA for cytokines Journal of investigative dermatology Medium 26039541
2018 Soluble CD74 (sCD74) co-treatment with MIF induces necroptosis in cardiac myofibroblasts via RIP1/RIP3-dependent mechanism; sCD74 diminishes MIF-mediated AKT activation and triggers p38 activation, rerouting survival signaling to necroptotic cell death specific to cardiac fibroblasts but not cardiomyocytes. Recombinant sCD74 and MIF co-treatment; RIP1/RIP3 inhibition assays; Western blot for AKT and p38 phosphorylation; microarray/RT-qPCR for interferon-induced genes; cell death quantification Journal of the American Heart Association Medium 30371153
2020 CD74 signaling in intestinal epithelial cells is necessary for gut repair after colitis: MIF stimulates CD74 receptor, enhancing epithelial cell proliferation through activation of AKT and ERK pathways; CD74 signaling in immune cells was not essential for mucosal healing. CD74-/- mice and bone marrow chimera models; CRISPR/Cas9 CD74 knockout; anti-CD74 neutralizing antibodies; Western blot for phospho-AKT and phospho-ERK; immunohistochemistry; flow cytometry Cellular and molecular gastroenterology and hepatology High 32004754
2010 CD74 is expressed on normal colon epithelial cells; MIF stimulation of CD74 induces upregulation of Bcl-2 and increased survival of CEC from WT but not CD74-deficient mice; in CT26 colon carcinoma cells, MIF-CD74 signaling enhances cell survival, AKT phosphorylation, and Bcl-2 expression. RT-PCR, Western blot, FACS for CD74 expression; survival assays with CD74-KO mice CEC; Western blot for phospho-AKT and Bcl-2 World journal of gastroenterology Medium 20614481
2014 The HLA-DRα1 domain directly inhibits binding of MIF to CD74, blocking downstream inflammatory ERK1/2 signaling in the spinal cord in EAE; a single amino acid substitution (L50Q) enhances DRα1 affinity for CD74, increases MIF binding blockade, and improves therapeutic activity, identifying the MIF-binding region on CD74. MIF-CD74 binding competition assay; in vivo EAE mouse model; Western blot for pERK1/2; trypsin digestion functional assay; histological analysis Journal of immunology Medium 24683185 30353480
2016 CD74-NRG1 fusion promotes cancer stem cell-like properties via ErbB2/3 phosphorylation, activating PI3K/Akt/NF-κB, which in an NF-κB-dependent manner upregulates IGF2 secretion and IGF1R phosphorylation, establishing an IGF2 autocrine/paracrine circuit; inhibition of ErbB2, PI3K, NF-κB, or IGF2 suppresses tumor sphere formation. Ectopic expression of CD74-NRG1 in lung epithelial cells; Western blot for phospho-ErbB2/3, phospho-Akt, NF-κB; sphere formation assay; limiting dilution xenograft; NF-κB reporter; IGF2/IGF1R ELISA and Western blot; pharmacological inhibition Cancer research Medium 26837769
2022 CD74-NRG1 physically binds ERBB3, and this interaction drives ERBB2:ERBB3 heterodimerization as the mechanistic event in transformation; CD74-NRG1-expressing cells proliferate independent of exogenous NRG1 ligand; transgenic mice ubiquitously expressing CD74-NRG1 develop tumors at high frequency. CD74-NRG1 transgenic mouse model; ERBB3 binding assay; Western blot for phospho-ERBB2/ERBB3; proliferation assays in the absence of NRG1; pharmacological ERBB2/3 inhibition Molecular cancer therapeutics High 35247925
2019 MIF-CD74 interaction directly regulates PD-L1 expression in melanoma: IFN-γ upregulates CD74 surface expression; blockade of CD74-MIF interaction with 4-IPP inhibitor or siRNA knockdown of MIF or CD74 suppresses PD-L1 expression; constitutive PD-L1 expression in WM1361A melanoma cells is also dependent on MIF-CD74. siRNA knockdown of CD74 and MIF; 4-IPP pharmacological inhibition; Western blot and flow cytometry for PD-L1; immunohistochemistry in patient melanoma tissues Cancer science Medium 31069878
2021 CD74 absence in mice leads to accumulation of hematopoietic stem cells (HSCs) in bone marrow due to increased repopulation potential and competition for BM niches; CD74-KO HSCs show increased survival and accumulation of both quiescent and proliferating cells; CD74 regulates CD18 expression on HSCs. In vitro CD74 blockade elevated HSPC numbers. CD74-KO mouse analysis; competitive repopulation assays; BM transplantation; flow cytometry for HSC populations; in vitro HSPC expansion with CD74 blockade PLoS biology High 33661886
2016 CD74 silencing in macrophages diminishes adhesion molecule expression (ALCAM, ICAM4, Syndecan-2), reduces macrophage adhesion to trophoblasts, and shifts macrophage activation toward a pro-inflammatory signature with increased TNF-α, CCL5, and MCP-1 secretion; CD74-KO mice display disturbed placental morphology, reduced junctional zone, impaired spiral artery remodeling, and fetal growth restriction. CD74 siRNA silencing in macrophages; co-culture of macrophages with trophoblasts; flow cytometry and RT-PCR; CD74-KO mouse placental analysis; immunofluorescence Circulation research High 27199465
2019 MIF activates CD74 on atrial cardiomyocytes to increase calcium transients, SR calcium content, NCX efflux, calcium leak, and potassium currents; MIF induces SERCA, NCX, and phosphorylation of RyR2 and activates CaMKII; these electrophysiological effects and CaMKII-RyR2 signaling activation are attenuated by anti-CD74 neutralizing antibody. Patch clamp electrophysiology; confocal fluorescence microscopy for calcium; Western blot for signaling proteins; anti-CD74 neutralizing antibody treatment; electrocardiographic telemetry in MIF-injected mice Translational research Medium 31669150
2020 CD74 ablation protects against LPS-induced cardiac dysfunction through suppression of autophagy via an AMPK-Skp2-SUV39H1-mediated mechanism: CD74-KO reverses LPS-induced Skp2 downregulation and SUV39H1/H3K9 methylation of BCLB; AMPK activator or rapamycin nullifies CD74 KO protection. CD74-KO mouse echocardiography; cardiomyocyte contractile function assay; Western blot for AMPK, mTOR, Skp2, SUV39H1, H3K9 methylation; GFP-LC3B autophagy reporter; pharmacological inhibitors (AICAR, rapamycin, chaetocin) British journal of pharmacology Medium 31877229
2023 TIMP-1 shares CD74-binding residues with MIF and MIF-2 (but not CXCR4-binding residues); TIMP-1 interacts with surface-expressed CD74 causing its internalization, and activates AKT and ERK1/2 phosphorylation in monocytes via CD74; this TIMP-1-CD74 axis promotes monocyte recruitment responses and VSMC proliferation. Sequence alignment and in silico docking; subcellular colocalization; co-immunoprecipitation; internalization assay; phospho-kinase array; AKT/ERK Western blot; Transwell migration and flow adhesion assays; live cell imaging for VSMC proliferation Cells Medium 37508563
2024 CD74 is upregulated on activated CD4+ T cells post-translationally modified by chondroitin sulfate and traffics to the cell surface; proximity ligation assay demonstrates CD74/CXCR4 heterocomplexes on activated T cells that diminish after MIF treatment, indicating MIF-induced internalization; CD74 and CXCR4 cooperatively mediate MIF-induced T cell migration. Flow cytometry; Western blot; immunohistochemistry; proximity ligation assay; 3D-matrix live cell imaging; receptor pathway-specific inhibitors; re-analysis of RNA-seq and proteomics data Cellular and molecular life sciences Medium 38992165
2024 Genetic deletion of CD74 in human primary Tregs causes major defects in actin cytoskeleton organization and intracellular organelle arrangement; intratumoral CD74-KO Tregs show decreased activation, reduced Foxp3 expression, and impaired accumulation in tumors, leading to accelerated tumor rejection in preclinical models; CD74 effects are tumor-specific and do not affect Treg phenotype or suppressive capacity at steady state. CD74 genetic deletion in human primary Tregs (CRISPR); actin cytoskeleton imaging; flow cytometry for activation markers and Foxp3; intratumoral Treg accumulation assays; preclinical mouse tumor models Nature communications High 38702311
2024 APP on GBM tumor cell surfaces binds the CD74/CXCR4 receptor complex on tumor-associated macrophages, promoting phosphorylation of SHP-1 and thereby inhibiting TAM phagocytosis; disrupting the APP-CD74 axis upregulates TAM phagocytosis in vitro and in vivo. Cell-cell communication analysis (scRNA-seq); co-immunoprecipitation; SHP-1 phosphorylation Western blot; phagocytosis assays in vitro and in vivo Biochimica et biophysica acta. Molecular basis of disease Medium 39111632
2024 In triple-negative breast cancer, MIF from tumor cells activates CD74 on dendritic cells, inducing CD74-ICD binding to the SP1 promoter, upregulating SP1, which binds the IL-1β promoter to downregulate IL-1β transcription; reduced IL-1β leads to expansion of tolerogenic DCs and regulatory B cells, suppressing anti-tumor immunity. CD74-KO mice; Cre-flox conditional KO in CD23+ B cells and CD11c+ DCs; CD74 inhibitor (DRQ); ChIP for CD74-ICD binding SP1 promoter; Western blot; flow cytometry for tol-DC and Breg populations; tumor growth assays PLoS biology High 39576827
2024 CD74 functions as a transcriptional factor in ADPKD: CD74 binds promoters of fibrotic markers (collagen I, fibronectin, α-SMA) to upregulate them; CD74 also binds the MIF promoter to form a positive feedback loop where MIF activates CD74 signaling and CD74 increases MIF expression; CD74-KO normalizes ERK, mTOR, and Rb signaling and reduces NF-κB/MCP-1/TNF-α-dependent macrophage recruitment. CD74-KO in Pkd1 mutant mice; ChIP for CD74 binding fibrotic gene promoters and MIF promoter; Western blot for ERK/mTOR/Rb/NF-κB; ELISA for MCP-1/TNF-α; histology for macrophage recruitment and fibrosis; cell proliferation assays Cells High 38534333
2025 CD74 signaling drives inflammation in RUNX1-FPD hematopoietic stem/progenitor cells through activation of mTOR and JAK/STAT pathways with increased cytokine production; genetic and pharmacological CD74 targeting (ISO-1) reverses myeloid-biased differentiation defects and reduces inflammation both in vitro and in vivo. Single-cell RNA sequencing of patient FPD samples; Western blot and phospho-flow for mTOR/JAK/STAT; CD74 genetic targeting; ISO-1 pharmacological inhibition; in vitro and in vivo differentiation assays; cytokine profiling Science translational medicine Medium 39772771
2016 Predicted structural modeling of MIF/CD74 interaction reveals 3 binding sites on the MIF homotrimer each engaging one CD74 trimer through two distinct 5-amino-acid determinants, forming a predicted MIF(CD74)3 dodecamer; the same CD74 determinants are used by the competitive inhibitor RTL1000. In silico protein-protein docking of MIF trimer and CD74 trimer; structural modeling of CD74-RTL1000 complex Metabolic brain disease Low 26851955
2022 The CD74 p41 splice isoform specifically inhibits cathepsin L (CTSL) activity; in arthritis, the p41 isoform is differentially expressed in severely affected tissue and correlates with TNF expression; M1-like macrophages express higher CD74 and have higher CTSL secretion/activity than M2-like macrophages; RA patients responding to TNF blockade show higher CD74 in circulating monocytes post-treatment. qPCR for CD74 isoforms; CTSL enzymatic activity assay; macrophage polarization in vitro; flow cytometry; collagen-induced arthritis mouse model Journal of autoimmunity Medium 35245865
2011 FTY720 induces lysosomal membrane permeabilization and blocks autophagic-lysosomal degradation, leading to increased CD74 levels; CD74 is normally degraded in the lysosomal compartment. Western blot for CD74, LC3-II, and p62; fluorescence microscopy for autolysosomes; lysosomal hydrolase translocation assay in MCL cell lines Blood Medium 22042694
2014 CD74 suppression in lymphoma cells (BJAB, Raji) increases surface Fas receptor expression, enhances caspase-8 and caspase-3 cleavage upon FasL stimulation, and sensitizes cells to Fas-mediated apoptosis and chemotherapy; conversely, full-length CD74 overexpression in livers protects mice from lethal anti-Fas challenge, indicating CD74 interferes with early Fas signaling at the plasma membrane. shRNA-mediated CD74 knockdown; hydrodynamic transfection with full-length CD74 in mice; flow cytometry for Fas surface expression; Western blot for caspase-8/-3 cleavage; FasL challenge survival assay Journal of experimental & clinical cancer research Medium 25304249
2005 Gastric epithelial cells constitutively express CD74 (invariant chain) mRNA and all protein isoforms; CD74 surface expression is polarized to the apical surface of these non-conventional antigen-presenting cells, as determined by immunohistochemistry on human biopsies and multiple gastric epithelial cell lines. RT-PCR for CD74 mRNA; Western blot for CD74 isoforms; immunohistochemistry and immunofluorescence on human gastric biopsies and cell lines; polarized expression confirmed by confocal imaging Journal of histochemistry and cytochemistry Medium 15923369

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Cell-surface CD74 initiates a signaling cascade leading to cell proliferation and survival. Blood 249 16484589
2016 The biological function and significance of CD74 in immune diseases. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 246 27752708
2014 CD74-NRG1 fusions in lung adenocarcinoma. Cancer discovery 238 24469108
2016 The multifaceted roles of the invariant chain CD74--More than just a chaperone. Biochimica et biophysica acta 213 27033518
2009 A functional heteromeric MIF receptor formed by CD74 and CXCR4. FEBS letters 202 19665027
2007 CD74: a new candidate target for the immunotherapy of B-cell neoplasms. Clinical cancer research : an official journal of the American Association for Cancer Research 183 17875789
2011 CD74: an emerging opportunity as a therapeutic target in cancer and autoimmune disease. Expert opinion on therapeutic targets 138 21208136
2014 MIF promotes B cell chemotaxis through the receptors CXCR4 and CD74 and ZAP-70 signaling. Journal of immunology (Baltimore, Md. : 1950) 136 24760155
2020 Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair. Frontiers in immunology 134 32655566
2016 CD74 is a novel transcription regulator. Proceedings of the National Academy of Sciences of the United States of America 121 28031488
2004 CD74 is expressed by multiple myeloma and is a promising target for therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 118 15475450
2016 MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis. Oncogene 117 27157615
2008 The MIF receptor CD74 in diabetic podocyte injury. Journal of the American Society of Nephrology : JASN 101 18842989
2009 CD74 in antigen presentation, inflammation, and cancers of the gastrointestinal tract. World journal of gastroenterology 88 19533806
2020 CD74 Signaling Links Inflammation to Intestinal Epithelial Cell Regeneration and Promotes Mucosal Healing. Cellular and molecular gastroenterology and hepatology 72 32004754
2016 CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia. Circulation research 72 27199465
2009 Expression of CD74, the receptor for macrophage migration inhibitory factor, in non-small cell lung cancer. The American journal of pathology 72 19131591
2007 CD74 induces TAp63 expression leading to B-cell survival. Blood 72 17846227
2015 Cell Surface CD74-MIF Interactions Drive Melanoma Survival in Response to Interferon-γ. The Journal of investigative dermatology 65 26039541
2012 MIF, CD74 and other partners in kidney disease: tales of a promiscuous couple. Cytokine & growth factor reviews 64 22959722
2022 CD74 ablation rescues type 2 diabetes mellitus-induced cardiac remodeling and contractile dysfunction through pyroptosis-evoked regulation of ferroptosis. Pharmacological research 61 35033649
2012 CD74 and macrophage migration inhibitory factor as therapeutic targets in gastric cancer. World journal of gastroenterology 61 22611320
2014 The integral role of CD74 in antigen presentation, MIF signal transduction, and B cell survival and homeostasis. Mini reviews in medicinal chemistry 59 25643611
2016 Oncogenic Fusion Gene CD74-NRG1 Confers Cancer Stem Cell-like Properties in Lung Cancer through a IGF2 Autocrine/Paracrine Circuit. Cancer research 57 26837769
2024 Blocking the MIF-CD74 axis augments radiotherapy efficacy for brain metastasis in NSCLC via synergistically promoting microglia M1 polarization. Journal of experimental & clinical cancer research : CR 56 38685050
2018 Soluble CD74 Reroutes MIF/CXCR4/AKT-Mediated Survival of Cardiac Myofibroblasts to Necroptosis. Journal of the American Heart Association 54 30371153
2011 Role for CD74 and CXCR4 in clathrin-dependent endocytosis of the cytokine MIF. European journal of cell biology 53 22014447
2022 Interplay between soluble CD74 and macrophage-migration inhibitory factor drives tumor growth and influences patient survival in melanoma. Cell death & disease 52 35121729
2017 MIF/CD74 axis is a target for novel therapies in colon carcinomatosis. Journal of experimental & clinical cancer research : CR 49 28114961
2024 CD74 is a functional MIF receptor on activated CD4+ T cells. Cellular and molecular life sciences : CMLS 46 38992165
2021 CD74 and CD44 Expression on CTCs in Cancer Patients with Brain Metastasis. International journal of molecular sciences 46 34209696
2011 FTY720 increases CD74 expression and sensitizes mantle cell lymphoma cells to milatuzumab-mediated cell death. Blood 46 22042694
2014 Involvement of macrophage migration inhibitory factor and its receptor (CD74) in human breast cancer. Oncology reports 45 24939415
2024 CD74 supports accumulation and function of regulatory T cells in tumors. Nature communications 44 38702311
2014 HLA-DRα1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis. Journal of immunology (Baltimore, Md. : 1950) 44 24683185
2017 CD74 and intratumoral immune response in breast cancer. Oncotarget 43 27058619
2022 CD74 as a regulator of transcription in normal B cells. Cell reports 42 36323260
2017 Association between mRNA expression of CD74 and IL10 and risk of ICU-acquired infections: a multicenter cohort study. Intensive care medicine 42 28477143
2019 Macrophage migration inhibitory factor-CD74 interaction regulates the expression of programmed cell death ligand 1 in melanoma cells. Cancer science 41 31069878
2013 Deletion of CD74, a putative MIF receptor, in mice enhances osteoclastogenesis and decreases bone mass. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 41 23044992
2011 The secret second life of an innocent chaperone: the story of CD74 and B cell/chronic lymphocytic leukemia cell survival. Leukemia & lymphoma 40 21417823
2010 CD74 is a survival receptor on colon epithelial cells. World journal of gastroenterology 40 20614481
2019 YAP1 promotes multidrug resistance of small cell lung cancer by CD74-related signaling pathways. Cancer medicine 39 31692299
2015 CD74 in Kidney Disease. Frontiers in immunology 38 26441987
2016 Predicted structure of MIF/CD74 and RTL1000/CD74 complexes. Metabolic brain disease 37 26851955
2020 CD74 knockout protects against LPS-induced myocardial contractile dysfunction through AMPK-Skp2-SUV39H1-mediated demethylation of BCLB. British journal of pharmacology 36 31877229
2011 Expression of macrophage migration inhibitory factor and CD74 in cervical squamous cell carcinoma. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 35 21792010
2014 Involvement of CD74 in head and neck squamous cell carcinomas. Journal of cancer research and clinical oncology 34 24663824
2014 MIF and CD74 - suitability as clinical biomarkers. Mini reviews in medicinal chemistry 34 25643609
2010 Enhanced expression of CD74 in gastrointestinal cancers and benign tissues. International journal of clinical and experimental pathology 34 21228923
2015 CD74 expression and its therapeutic potential in thyroid carcinoma. Endocrine-related cancer 33 25600560
2016 Relationship between elevated soluble CD74 and severity of experimental and clinical ALI/ARDS. Scientific reports 32 27444250
2024 Targeting tumor-associated macrophage-derived CD74 improves efficacy of neoadjuvant chemotherapy in combination with PD-1 blockade for cervical cancer. Journal for immunotherapy of cancer 31 39107132
2018 LPS-mediated cell surface expression of CD74 promotes the proliferation of B cells in response to MIF. Cellular signalling 31 29476963
2021 CD74 Correlated With Malignancies and Immune Microenvironment in Gliomas. Frontiers in molecular biosciences 29 34540893
2024 Therapeutic modulation of APP-CD74 axis can activate phagocytosis of TAMs in GBM. Biochimica et biophysica acta. Molecular basis of disease 28 39111632
2024 Single-cell transcriptomic analysis reveals that the APP-CD74 axis promotes immunosuppression and progression of testicular tumors. The Journal of pathology 27 39161125
2019 CD74 knockout attenuates alcohol intake-induced cardiac dysfunction through AMPK-Skp2-mediated regulation of autophagy. Biochimica et biophysica acta. Molecular basis of disease 26 31167126
2018 High frequency of CD74 expression in lymphomas: implications for targeted therapy using a novel anti-CD74-drug conjugate. The journal of pathology. Clinical research 26 30191677
2005 Polarized expression of CD74 by gastric epithelial cells. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 26 15923369
2024 MIF and CD74 as Emerging Biomarkers for Immune Checkpoint Blockade Therapy. Cancers 25 38730725
2021 CD74 is a regulator of hematopoietic stem cell maintenance. PLoS biology 25 33661886
2024 APP-CD74 axis mediates endothelial cell-macrophage communication to promote kidney injury and fibrosis. Frontiers in pharmacology 24 39351084
2022 Role of MIF1/MIF2/CD74 interactions in bladder cancer. The Journal of pathology 23 36214539
2017 CD74 Deficiency Mitigates Systemic Lupus Erythematosus-like Autoimmunity and Pathological Findings in Mice. Journal of immunology (Baltimore, Md. : 1950) 23 28219888
2024 CD74 promotes the formation of an immunosuppressive tumor microenvironment in triple-negative breast cancer in mice by inducing the expansion of tolerogenic dendritic cells and regulatory B cells. PLoS biology 22 39576827
2019 Macrophage migration inhibitory factor increases atrial arrhythmogenesis through CD74 signaling. Translational research : the journal of laboratory and clinical medicine 21 31669150
2018 Jun, Gal, Cd74, and C1qb as potential indicator for neuropathic pain. Journal of cellular biochemistry 21 29331040
2012 CD74 expression is increased in high-grade, invasive urothelial carcinoma of the bladder. International journal of urology : official journal of the Japanese Urological Association 20 22905972
2022 Microglial CD74 Expression Is Regulated by TGFβ Signaling. International journal of molecular sciences 19 36142162
2024 IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHCII complexes. Science advances 18 38996030
2024 Single-cell transcriptome analysis deciphers the CD74-mediated immune evasion and tumour growth in lung squamous cell carcinoma with chronic obstructive pulmonary disease. Clinical and translational medicine 18 39113235
2023 Infection and inflammation stimulate expansion of a CD74+ Paneth cell subset to regulate disease progression. The EMBO journal 18 37718683
2023 Single-cell RNA-seq reveals MIF-(CD74 + CXCR4) dependent inhibition of macrophages in metastatic papillary thyroid carcinoma. Oral oncology 18 38061122
2023 CD74/SLC34A2-ROS1 Fusion Variants Involving the Transmembrane Region Predict Poor Response to Crizotinib in NSCLC Independent of TP53 Mutations. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 18 38070598
2022 CD74 and HLA-DRA in Cervical Carcinogenesis: Potential Targets for Antitumour Therapy. Medicina (Kaunas, Lithuania) 18 35208514
2013 CD74-ROS1 fusion transcripts in resected non-small cell lung carcinoma. Oncology reports 18 23877438
2023 The role of CD74 in cardiovascular disease. Frontiers in cardiovascular medicine 17 36712241
2023 CD74 Promotes a Pro-Inflammatory Tumor Microenvironment by Inducing S100A8 and S100A9 Secretion in Pancreatic Cancer. International journal of molecular sciences 17 37629174
2010 Suppression of CD74 expression and Helicobacter pylori adhesion by auraptene targeting serum starvation-activated ERK1/2 in NCI-N87 gastric carcinoma cells. Bioscience, biotechnology, and biochemistry 17 20460732
2024 The role of macrophage migration inhibitory factor family and CD74 in the pathogenesis of melanoma. Experimental dermatology 16 38884501
2023 A novel CAR-T cell product targeting CD74 is an effective therapeutic approach in preclinical mantle cell lymphoma models. Experimental hematology & oncology 16 37740214
2021 Canonical (CD74/CD44) and Non-Canonical (CXCR2, 4 and 7) MIF Receptors Are Differentially Expressed in Rheumatoid Arthritis Patients Evaluated by DAS28-ESR. Journal of clinical medicine 15 35011861
2025 Targeting the CD74 signaling axis suppresses inflammation and rescues defective hematopoiesis in RUNX1-familial platelet disorder. Science translational medicine 14 39772771
2023 Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation. Cells 14 37508563
2018 TWEAK increases CD74 expression and sensitizes to DDT proinflammatory actions in tubular cells. PloS one 14 29924850
2025 CD74 Blockade Disrupts Endothelial Migrasome Signaling to Prevent Inflammatory Macrophage Differentiation and Inhibit Atherosclerotic Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 13 40548932
2023 Macrophage migration inhibitory factor receptor CD74 expression is associated with expansion and differentiation of effector T cells in COVID-19 patients. Frontiers in immunology 13 37946732
2022 CD74 in Apoptotic Macrophages Is Associated with Inflammation, Plaque Progression and Clinical Manifestations in Human Atherosclerotic Lesions. Metabolites 13 35050177
2022 Disease status in human and experimental arthritis, and response to TNF blockade, is associated with MHC class II invariant chain (CD74) isoform expression. Journal of autoimmunity 13 35245865
2022 CXCR4 and CD74 together enhance cell survival in response to macrophage migration-inhibitory factor in chronic lymphocytic leukemia. Experimental hematology 13 36096455
2014 CD74 interferes with the expression of fas receptor on the surface of lymphoma cells. Journal of experimental & clinical cancer research : CR 13 25304249
2025 Integrative analysis of Ewing's sarcoma reveals that the MIF-CD74 axis is a target for immunotherapy. Cell communication and signaling : CCS 12 39800691
2021 A deficient MIF-CD74 signaling pathway may play an important role in immunotherapy-induced hyper-progressive disease. Cell biology and toxicology 12 34797429
2019 CD74 is a T cell antigen in spondyloarthritis. Clinical and experimental rheumatology 12 31140396
2024 CD74 Promotes Cyst Growth and Renal Fibrosis in Autosomal Dominant Polycystic Kidney Disease. Cells 11 38534333
2023 Targeting CD74 in B-cell non-Hodgkin lymphoma with the antibody-drug conjugate STRO-001. Oncotarget 11 36634212
2023 Analysis of CD74 Occurrence in Oncogenic Fusion Proteins. International journal of molecular sciences 11 37958963
2022 CD74-NRG1 Fusions Are Oncogenic In Vivo and Induce Therapeutically Tractable ERBB2:ERBB3 Heterodimerization. Molecular cancer therapeutics 11 35247925
2018 Increased CD74 binding and EAE treatment efficacy of a modified DRα1 molecular construct. Metabolic brain disease 11 30353480

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