Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

CD74 (CD74 molecule, major histocompatibility complex, class II invariant chain)

Written2014-03Naama Gil-Yarom, Shirly Becker Herman, Idit Shachar
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel

(Note : for Links provided by Atlas : click)

Identity

Alias_namesDHLAG
CD74 antigen (invariant polypeptide of major histocompatibility complex, class II antigen-associated)
CD74 molecule, major histocompatibility complex, class II invariant chain
HGNC (Hugo) CD74
LocusID (NCBI) 972
Atlas_Id 45843
Location 5q32  [Link to chromosome band 5q32]
Location_base_pair Starts at 149781200 and ends at 149792499 bp from pter ( according to hg19-Feb_2009)  [Mapping CD74.png]
Fusion genes
(updated 2016)
ACTG1 (17q25.3) / CD74 (5q32)AHSG (3q27.3) / CD74 (5q32)CD74 (5q32) / ABLIM2 (4p16.1)
CD74 (5q32) / ASCC2 (22q12.2)CD74 (5q32) / AUTS2 (7q11.22)CD74 (5q32) / BPIFA2 (20q11.21)
CD74 (5q32) / CD74 (5q32)CD74 (5q32) / EPC2 (2q23.1)CD74 (5q32) / GPC3 (Xq26.2)
CD74 (5q32) / IGHG1 (14q32.33)CD74 (5q32) / JMJD7-PLA2G4B (15q15.1)CD74 (5q32) / LOC100507412 (-)
CD74 (5q32) / MBD6 (12q13.3)CD74 (5q32) / MMP3 (11q22.2)CD74 (5q32) / NGB (14q24.3)
CD74 (5q32) / NPIPB7 (16q23.1)CD74 (5q32) / NR6A1 (9q33.3)CD74 (5q32) / NRG1 (8p12)
CD74 (5q32) / NTRK1 (1q23.1)CD74 (5q32) / NUSAP1 (15q15.1)CD74 (5q32) / PHC2 (1p35.1)
CD74 (5q32) / PPM1M (3p21.2)CD74 (5q32) / PUM2 (2p24.1)CD74 (5q32) / ROS1 (6q22.1)
CD74 (5q32) / RPL29 (3p21.2)CD74 (5q32) / SGK1 (6q23.2)CD74 (5q32) / SMAD3 (15q22.33)
CD74 (5q32) / SOD2 (6q25.3)CD74 (5q32) / TPP1 (11p15.4)CD74 (5q32) / UBAC2 (13q32.3)
CREB5 (7p15.1) / CD74 (5q32)FGD2 (6p21.2) / CD74 (5q32)FOXN3 (14q31.3) / CD74 (5q32)
PRICKLE3 (Xp11.23) / CD74 (5q32)RAN (12q24.33) / CD74 (5q32)ROS1 (6q22.1) / CD74 (5q32)

DNA/RNA

 
  Transcript structure of human CD74 (Geer et al., 2010).
Description The CD74 gene consists of 9 exons, different transcripts results in four protein variants.
Transcription CD74 gene is processed into 4 different in-vivo know transcripts resulting from two different translation initiation sites and alternative splicing (Borghese and Clanchy, 2011; UniProt Consortium, 2013):
P43 - The longest isoform. Contains a longer cytoplasmic tail due to the use of an alternative translation initiation site, and a THY domain from alternative splicing.
P41 - Similar to the P43 isoform but does not contain the longer cytoplasmic tail.
P35 - Similar to the P43 isoform but does not contain the THY domain.
P33 - Does not contain not the longer cytoplasmic tail and not the THY domain.

Protein

 
  Schematic representation of a monomeric CD74, isoform p33.
Description CD74 is a non-polymorphic type II integral membrane protein. The most common isoform is p33, which is 296 aa long and has a molecular weight of 33 kDa. The protein consists of three parts, a 46 aa long N-terminus cytoplasmic tail, 26 aa long transmembranal domain and a 224 aa long luminal region. CD74 assembles to homotrimers immediately after synthesis.
Expression CD74 is mainly expressed in antigen presenting cells, endothelial cells and neuroglia cells.
Localisation Trimers of CD74 are expressed in the endoplasmic reticulum (ER), in association with MHC α and β chains. The complex is transported to the trans-Golgi and then diverted from the secretory pathway to the endocytic system and ultimately to acidic endosome or lysosome-like structures called MHC class II compartments (MIIC or CIIV). A small proportion of CD74 is modified by the addition of chondroitin sulfate (CD74-CS), and this form of CD74 is expressed on the cell surface (Stumptner-Cuvelette and Benaroch, 2002).
Function CD74 function has two main functions:
1) MHCII chaperon
MHC class II molecules are heterodimeric complexes that present foreign antigenic peptides on the cell surface of antigen-presenting cells (APCs) to CD4+ T cells. MHC class II synthesis and assembly begins in the endoplasmic reticulum (ER) with the non-covalent association of the MHC α and β chains with trimers of CD74. Three MHC class II α β dimers bind sequentially to a trimer of the CD74 to form a nonameric complex (αβCD74)3, which then exits the ER (Roche et al., 1991). After being transported to the trans-Golgi, the αβCD74 complex is diverted from the secretory pathway to the endocytic compartments. Once in the endocytic compartments, CD74 is proteolytically processed. CD74 lumenal domain undergoes a stepwise proteolytic cleavage, which results in a short class II-associated Ii chain peptide (CLIP), which remains in the MHC class II peptide grove (Neefjes et al., 1990; Roche and Cresswell, 1991; Stumptner-Cuvelette and Benaroch, 2002). The final step for MHC class II expression requires interaction of αβCLIP complexes with another class II-related αβ dimer, called HLA-DM. Binding of this molecule excludes the residual CLIP peptide, rendering the αβ dimers ultimately competent to bind antigenic peptides, which are mainly derived from internalized antigens and also are delivered to the endocytic pathway (Denzin and Cresswell, 1995; Ghosh et al., 1995). Thus, CD74 was thought to function mainly as MHC class II chaperone, which promotes ER exit of MHC class II molecules, directs them to endocytic compartments, prevents self-peptide binding in the ER and contributes to peptide editing in the MHC class II compartment (Matza et al., 2003).
2) CD74 as cell surface receptor
A small proportion of CD74 is modified by the addition of chondroitin sulfate (CD74-CS), and this form of CD74 is expressed on the cell surface (Matza et al., 2003; Naujokas et al., 1993). This cell surface expression of CD74 is not strictly dependent on class II MHC (Henne et al., 1995; Starlets et al., 2006), and numerous non-class II positive cells express CD74 where it can serve as a receptor for the initiation of different signaling cascades (Maharshak et al., 2010; Stumptner-Cuvelette and Benaroch, 2002). The cytokine, macrophage migration inhibitory factor (MIF), was found to be the natural ligand of CD74. MIF binds to the extracellular domain of CD74 with high affinity (KD = 1.40 × 10-9 M) and initiates a signaling cascade (Leng et al., 2003). CD74 forms a complex with CD44, which is essential for the MIF-induced signaling cascade (Gore et al., 2008; Shi et al., 2006).
In murine B cells, CD74 expression is directly involved in shaping the B cell repertoire by regulating mature B cell survival (Gore et al., 2008; Matza et al., 2003; Shachar and Flavell, 1996; Starlets et al., 2006). MIF binding to CD74 induces a signaling pathway that involves the Syk tyrosine kinase and the PI3K/Akt pathway (Gore et al., 2008; Starlets et al., 2006), induction of CD74 intramembrane cleavage, and the release of the CD74 intracellular domain (CD74-ICD) (Matza et al., 2002; Schneppenheim et al., 2013). CD74-ICD translocates to the nucleus where it induces activation of transcription mediated by the NF-κB p65/RelA homodimer and its co-activator, TAFII105, resulting in regulation of transcription of genes that control B cell proliferation and survival (Gore et al., 2008; Matza et al., 2001; Starlets et al., 2006). MIF was found to regulate cell entry into the S-phase in a CD74 and CD44-dependent fashion, by elevating cyclin E levels, resulting in cell proliferation. In addition, this cascade augments Bcl-2 expression, further supporting cell survival (Cohen et al., 2012; Gordin et al., 2010; Gore et al., 2008; Lantner et al., 2007; Sapoznikov et al., 2008; Starlets et al., 2006). Thus, the MIF binding to CD74/CD44 complex initiates a pathway, resulting in proliferation of the mature B cell population, and their rescue from death.

Implicated in

Note
Entity Chronic lymphocytic leukaemia (CLL)
Prognosis CD74 and its ligand, MIF, were shown to play a pivotal role in the regulation of CLL cell survival. CLL cells markedly upregulate both expression of their cell surface CD74, and their MIF production. Stimulation of CD74 with the MIF ligand (as well as with an agonistic antibody) initiates a signaling cascade leading to IL-8 transcription and secretion in all CLL cells, regardless of the clinical status of the patients. Secreted IL-8 induces the transcription and translation of the anti-apoptotic protein, Bcl-2, and thus regulates an anti-apoptotic pathway. Blocking of CD74 (by milatuzumab), or of MIF or IL-8 results in dramatic downregulation of Bcl-2 expression, and augmentation of apoptosis (Binsky et al., 2007).
In addition, stimulation of CD74 with its natural ligand, MIF, initiates a signaling cascade that results in upregulation of TAp63, which directly regulates CLL survival. TAp63 expression also elevates the expression of the integrin VLA-4, particularly during the advanced stage of the disease. Blocking of CD74, TAp63, or VLA-4 inhibits the in vivo homing of CLL cells to the bone marrow (BM). Thus, CD74 and its target genes TAp63 and VLA-4 facilitate migration of CLL cells back to the BM, where they interact with the supportive BM environment that rescues them from apoptosis (Binsky et al., 2010).
 
CD74 activation by MIF up regulates cell survival and VLA-4 expression.
  
Entity Multiple myeloma (MM)
Prognosis CD74 expression was observed in 19 of 22 cases of multiple myeloma, with most expressing moderate to high levels in the majority of malignant plasma cells (Burton et al., 2004). CD74, expressed in MM, was evaluated as a target for immunotherapy with milatuzumab (a humanized anti-CD74 antibody). In a multicentre dose escalation study, 25 patients with advanced MM received milatuzumab doses of 1.5 (N = 8), 4.0 (N = 9), 8.0 (N = 4) or 16.0 mg/kg (N = 4) administered twice weekly x 4. They had a median of 5 prior treatments (17 post ≥ 1 stem cell transplantation) and were refractory (N = 7) or relapsed (N = 18) with generally short-lived responses to last treatment (median 4.0 months). After increasing prophylactic medications and slowing administration, infusions were well tolerated (National Cancer Institute-Common Terminology Criteria v3 toxicity Grades 1-2) with no dose-limiting toxicity at higher doses. Only one patient developed borderline positive human anti-milatuzumab antibody titres of uncertain clinical significance. Although milatuzumab was rapidly cleared from circulation with little serum accumulation and low trough levels, B-cell levels were moderately decreased with treatment (median decrease, 34%). Disease stabilization and evidence of pharmacodynamic activity support further development for use in combination with other agents or as a drug conjugate (Kaufman et al., 2013).
  
Entity Mantle cell lymphoma (MCL)
Prognosis CD74 is expressed on MCL. The combination of milatuzumab and rituximab has preclinical in vitro and in vivo activity in MCL (Alinari et al., 2011). Treatment of MCL cell lines and primary patient tumor cells with immobilized milatuzumab resulted in statistically significant enhanced cell death (Alinari et al., 2012).
  
Entity Non-Hodgkin lymphoma (NHL)
Prognosis Preclinical studies of the humanized anti-CD74 mAb hLL1 have shown that it is an effective therapeutic agent that may be of significant value for treatment of NHL (Stein et al., 2007).
  
Entity Invasive carcinoma of the bladder
Prognosis CD74 expression is increased in high-grade, invasive carcinoma of the bladder. Its expression was significantly associated with older age at diagnosis (Choi et al., 2013).
  
Entity Gastrointestinal carcinoma
Prognosis Expression of CD74 within gastrointestinal carcinomas showed a statistically greater expression than in the normal tissue counterparts. CD74 expression was observed in 95% of pancreatic carcinomas with the majority of cases presenting a mostly intense, diffuse labeling pattern. The results suggested a trend towards greater expression within the higher-grade carcinomas. Colorectal and gastric carcinomas gave similar results with 60% and 86%, respectively, positive for CD74 with an intense, diffuse staining pattern. For PanIN lesions there was greater expression of CD74 within higher grade, PanIN-3 lesions, whereas the colonic adenomas showed no such trend, but overall, a higher frequency and intensity of CD74 labeling than was observed within the colon carcinomas. These findings are supportive of a role for CD74 in the development and maintenance of gastrointestinal neo-plasia, and provide a rationale for development of therapeutic agents that are able to block CD74 function, specifically within the tumor cell (Gold et al., 2010).
  
Entity Non-small cell lung cancer
Prognosis CD74 was found to be expressed on non-small cell lung cancer (NSCLC) cells (Ioachim et al., 1996). CD74 immunoreactivity was present in the stromal cells in most tumors. However, in many tumors the malignant cells themselves also strongly expressed CD74 (McClelland et al., 2009).
  
Entity Thymic epithelial neoplasms
Prognosis Sixty-four thymic epithelial neoplasms (27 cases of benign thymoma, 20 cases of invasive thymoma, and 17 cases of true thymic carcinoma) were studied for neoplastic epithelial cell expression of CD74 and MHC class II molecules by immunohistochemical staining of paraffin-embedded tissue. Neoplastic epithelial cells in 88% of thymic carcinomas (15/17), 70% of invasive thymomas (14/20), but only 33% of benign thymomas (9/27) were immunoreactive for CD74. A subset of CD74-positive neoplasms was positive for MHC class II as well, with higher relative rates of dual positivity in more aggressive neoplasms. In addition, specific histologic subtypes of thymic epithelial neoplasms displayed differing patterns of CD74 positivity. Based on these findings, CD74 and MHC class II are useful markers for the classification of thymic epithelial neoplasms (Datta et al., 2000).
  
Entity Pancreatic cancer
Prognosis Pancreatic ductal adenocarcinoma (PDAC) is still one of the most fatal cancers. Sixty-eight patients receiving curative extended resection combined with preoperative chemoradiation and postoperative chemotherapy for primary PDAC were selected. Immunohistochemistry using anti-CD74 antibody on paraffin-embedded tissue samples was performed, and cases were divided into two groups according to the ratio of CD74-positive cells: expression level I, CD74-positive cells <70%; level II, CD74-positive cells >or=70%. The correlation of CD74 expression level with clinicopathological features and overall survival was evaluated. Forty-seven (69.1%) and 21 (30.9%) patients showed level I and II CD74 expression, respectively. Patients with level I CD74 expression had a significantly better survival rate than those with level II (P = 0.003). Among the patients with pathological tumor-node-metastasis stages I and II, those with level I CD74 expression showed a significantly better prognosis than those with level II (P = 0.006). CD74 expression proved as a useful prognostic indicator for PDAC treated with multimodal therapy (Nagata et al., 2009).
  
Entity Atherosclerosis
Prognosis Overexpression of CD74 has been reported in atherosclerotic plaques. Stimulation of CD74 with an anti-CD74 antibody, which binds the CD74 extracellular domain, induces the expression of the NF-κB-regulated gene MCP-1, a small cytokine that belongs to the CC chemokine family. MCP-1 recruits monocytes, memory T cells, and dendritic cells to the sites of inflammation (Martín-Ventura et al., 2009).
 
Schematic representation of the potential mechanisms by which CD74 is involved in MCP-1. induction.
  
Entity Alzheimer
Prognosis CD74 has been found to be upregulated in the microglia and neurons of Alzheimer's patients and can interact with the amyloid precursor protein, potentially inhibiting the production of amyloid-β.
  
Entity HIV
Prognosis HIV-1 gp41 binds directly to CD74 in HIV-1-infected cells, leading to ERK1/ERK2 MAPK activation and enhanced HIV-1 infection (Zhou et al., 2011). The cytoplasmic region of HIV-1 Vpu also was found to interact with the 30-amino-acid cytoplasmic tail of CD74. Human monocytic U937 cells infected with wild-type or Vpu-defective HIV-1 showed that Vpu down-regulated the surface expression of MHC class II molecules (Hussain et al., 2008).
  
Entity Gastric ulceration
Prognosis The pathogenic bacterium, Helicobacter pylori, was shown to bind to CD74 on gastric epithelial cells. Upon H. pylori binding to CD74, NF-κB activation occurs resulting in the production of proinflammatory cytokines, including IL-8. IL-8 plays a major role in the proinflammatory immune response to H. pylori infection, and the interaction of H. pylori with the gastric epithelial cells might be of critical importance in the immune response to this infection and the development of gastric ulceration (Beswick et al., 2005).
  

Bibliography

Novel targeted therapies for mantle cell lymphoma.
Alinari L, Christian B, Baiocchi RA.
Oncotarget. 2012 Feb;3(2):203-11.
PMID 22361516
 
Combination anti-CD74 (milatuzumab) and anti-CD20 (rituximab) monoclonal antibody therapy has in vitro and in vivo activity in mantle cell lymphoma.
Alinari L, Yu B, Christian BA, Yan F, Shin J, Lapalombella R, Hertlein E, Lustberg ME, Quinion C, Zhang X, Lozanski G, Muthusamy N, Praetorius-Ibba M, O'Connor OA, Goldenberg DM, Byrd JC, Blum KA, Baiocchi RA.
Blood. 2011 Apr 28;117(17):4530-41. doi: 10.1182/blood-2010-08-303354. Epub 2011 Jan 12.
PMID 21228331
 
CD74 is a member of the regulated intramembrane proteolysis-processed protein family.
Becker-Herman S, Arie G, Medvedovsky H, Kerem A, Shachar I.
Mol Biol Cell. 2005 Nov;16(11):5061-9. Epub 2005 Aug 17.
PMID 16107560
 
Helicobacter pylori binds to CD74 on gastric epithelial cells and stimulates interleukin-8 production.
Beswick EJ, Bland DA, Suarez G, Barrera CA, Fan X, Reyes VE.
Infect Immun. 2005 May;73(5):2736-43.
PMID 15845476
 
IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival.
Binsky I, Haran M, Starlets D, Gore Y, Lantner F, Harpaz N, Leng L, Goldenberg DM, Shvidel L, Berrebi A, Bucala R, Shachar I.
Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13408-13. Epub 2007 Aug 8.
PMID 17686984
 
TAp63 regulates VLA-4 expression and chronic lymphocytic leukemia cell migration to the bone marrow in a CD74-dependent manner.
Binsky I, Lantner F, Grabovsky V, Harpaz N, Shvidel L, Berrebi A, Goldenberg DM, Leng L, Bucala R, Alon R, Haran M, Shachar I.
J Immunol. 2010 May 1;184(9):4761-9. doi: 10.4049/jimmunol.0904149. Epub 2010 Mar 31.
PMID 20357260
 
CD74: an emerging opportunity as a therapeutic target in cancer and autoimmune disease.
Borghese F, Clanchy FI.
Expert Opin Ther Targets. 2011 Mar;15(3):237-51. doi: 10.1517/14728222.2011.550879. Epub 2011 Jan 6. (REVIEW)
PMID 21208136
 
CD74 is expressed by multiple myeloma and is a promising target for therapy.
Burton JD, Ely S, Reddy PK, Stein R, Gold DV, Cardillo TM, Goldenberg DM.
Clin Cancer Res. 2004 Oct 1;10(19):6606-11.
PMID 15475450
 
CD74 expression is increased in high-grade, invasive urothelial carcinoma of the bladder.
Choi JW, Kim Y, Lee JH, Kim YS.
Int J Urol. 2013 Feb;20(2):251-5. doi: 10.1111/j.1442-2042.2012.03128.x. Epub 2012 Aug 21.
PMID 22905972
 
The cytokine midkine and its receptor RPTP? regulate B cell survival in a pathway induced by CD74.
Cohen S, Shoshana OY, Zelman-Toister E, Maharshak N, Binsky-Ehrenreich I, Gordin M, Hazan-Halevy I, Herishanu Y, Shvidel L, Haran M, Leng L, Bucala R, Harroch S, Shachar I.
J Immunol. 2012 Jan 1;188(1):259-69. doi: 10.4049/jimmunol.1101468. Epub 2011 Dec 2.
PMID 22140262
 
Expression of MHC class II-associated invariant chain (Ii;CD74) in thymic epithelial neoplasms.
Datta MW, Shahsafaei A, Nadler LM, Freeman GJ, Dorfman DM.
Appl Immunohistochem Mol Morphol. 2000 Sep;8(3):210-5.
PMID 10981873
 
HLA-DM induces CLIP dissociation from MHC class II alpha beta dimers and facilitates peptide loading.
Denzin LK, Cresswell P.
Cell. 1995 Jul 14;82(1):155-65.
PMID 7606781
 
The NCBI BioSystems database.
Geer LY, Marchler-Bauer A, Geer RC, Han L, He J, He S, Liu C, Shi W, Bryant SH.
Nucleic Acids Res. 2010 Jan;38(Database issue):D492-6. doi: 10.1093/nar/gkp858. Epub 2009 Oct 23.
PMID 19854944
 
The structure of an intermediate in class II MHC maturation: CLIP bound to HLA-DR3.
Ghosh P, Amaya M, Mellins E, Wiley DC.
Nature. 1995 Nov 30;378(6556):457-62.
PMID 7477400
 
Enhanced expression of CD74 in gastrointestinal cancers and benign tissues.
Gold DV, Stein R, Burton J, Goldenberg DM.
Int J Clin Exp Pathol. 2010 Nov 23;4(1):1-12.
PMID 21228923
 
c-Met and its ligand hepatocyte growth factor/scatter factor regulate mature B cell survival in a pathway induced by CD74.
Gordin M, Tesio M, Cohen S, Gore Y, Lantner F, Leng L, Bucala R, Shachar I.
J Immunol. 2010 Aug 15;185(4):2020-31. doi: 10.4049/jimmunol.0902566. Epub 2010 Jul 16.
PMID 20639480
 
Macrophage migration inhibitory factor induces B cell survival by activation of a CD74-CD44 receptor complex.
Gore Y, Starlets D, Maharshak N, Becker-Herman S, Kaneyuki U, Leng L, Bucala R, Shachar I.
J Biol Chem. 2008 Feb 1;283(5):2784-92. Epub 2007 Dec 4.
PMID 18056708
 
Circulating B-cell chronic lymphocytic leukemia cells display impaired migration to lymph nodes and bone marrow.
Hartmann TN, Grabovsky V, Wang W, Desch P, Rubenzer G, Wollner S, Binsky I, Vallon-Eberhard A, Sapoznikov A, Burger M, Shachar I, Haran M, Honczarenko M, Greil R, Alon R.
Cancer Res. 2009 Apr 1;69(7):3121-30. doi: 10.1158/0008-5472.CAN-08-4136. Epub 2009 Mar 17.
PMID 19293181
 
Surface expression of the invariant chain (CD74) is independent of concomitant expression of major histocompatibility complex class II antigens.
Henne C, Schwenk F, Koch N, Moller P.
Immunology. 1995 Feb;84(2):177-82.
PMID 7750992
 
The lysosomal cysteine proteases in MHC class II antigen presentation.
Hsing LC, Rudensky AY.
Immunol Rev. 2005 Oct;207:229-41. (REVIEW)
PMID 16181340
 
Human immunodeficiency virus type 1 Vpu protein interacts with CD74 and modulates major histocompatibility complex class II presentation.
Hussain A, Wesley C, Khalid M, Chaudhry A, Jameel S.
J Virol. 2008 Jan;82(2):893-902. Epub 2007 Oct 24.
PMID 17959659
 
Lymphoid monoclonal antibodies reactive with lung tumors. Diagnostic applications.
Ioachim HL, Pambuccian SE, Hekimgil M, Giancotti FR, Dorsett BH.
Am J Surg Pathol. 1996 Jan;20(1):64-71.
PMID 8540610
 
Peptide exchange in MHC molecules.
Jensen PE, Weber DA, Thayer WP, Westerman LE, Dao CT.
Immunol Rev. 1999 Dec;172:229-38. (REVIEW)
PMID 10631949
 
Phase I, multicentre, dose-escalation trial of monotherapy with milatuzumab (humanized anti-CD74 monoclonal antibody) in relapsed or refractory multiple myeloma.
Kaufman JL, Niesvizky R, Stadtmauer EA, Chanan-Khan A, Siegel D, Horne H, Wegener WA, Goldenberg DM.
Br J Haematol. 2013 Nov;163(4):478-86. doi: 10.1111/bjh.12565. Epub 2013 Sep 25.
PMID 24112026
 
CD74 induces TAp63 expression leading to B-cell survival.
Lantner F, Starlets D, Gore Y, Flaishon L, Yamit-Hezi A, Dikstein R, Leng L, Bucala R, Machluf Y, Oren M, Shachar I.
Blood. 2007 Dec 15;110(13):4303-11. Epub 2007 Sep 10.
PMID 17846227
 
MIF signal transduction initiated by binding to CD74.
Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, Delohery T, Chen Y, Mitchell RA, Bucala R.
J Exp Med. 2003 Jun 2;197(11):1467-76.
PMID 12782713
 
CD74 is a survival receptor on colon epithelial cells.
Maharshak N, Cohen S, Lantner F, Hart G, Leng L, Bucala R, Shachar I.
World J Gastroenterol. 2010 Jul 14;16(26):3258-66.
PMID 20614481
 
Increased CD74 expression in human atherosclerotic plaques: contribution to inflammatory responses in vascular cells.
Martin-Ventura JL, Madrigal-Matute J, Munoz-Garcia B, Blanco-Colio LM, Van Oostrom M, Zalba G, Fortuno A, Gomez-Guerrero C, Ortega L, Ortiz A, Diez J, Egido J.
Cardiovasc Res. 2009 Aug 1;83(3):586-94. doi: 10.1093/cvr/cvp141. Epub 2009 May 7.
PMID 19423618
 
Invariant chain, a chain of command.
Matza D, Kerem A, Shachar I.
Trends Immunol. 2003 May;24(5):264-8. (REVIEW)
PMID 12738421
 
Invariant chain induces B cell maturation by activating a TAF(II)105-NF-kappaB-dependent transcription program.
Matza D, Wolstein O, Dikstein R, Shachar I.
J Biol Chem. 2001 Jul 20;276(29):27203-6. Epub 2001 May 22.
PMID 11371575
 
Expression of CD74, the receptor for macrophage migration inhibitory factor, in non-small cell lung cancer.
McClelland M, Zhao L, Carskadon S, Arenberg D.
Am J Pathol. 2009 Feb;174(2):638-46. doi: 10.2353/ajpath.2009.080463. Epub 2009 Jan 8.
PMID 19131591
 
CD74 is a novel prognostic factor for patients with pancreatic cancer receiving multimodal therapy.
Nagata S, Jin YF, Yoshizato K, Tomoeda M, Song M, Iizuka N, Kitamura M, Takahashi H, Eguchi H, Ohigashi H, Ishikawa O, Tomita Y.
Ann Surg Oncol. 2009 Sep;16(9):2531-8. doi: 10.1245/s10434-009-0532-3. Epub 2009 Jun 5.
PMID 19499276
 
The chondroitin sulfate form of invariant chain can enhance stimulation of T cell responses through interaction with CD44.
Naujokas MF, Morin M, Anderson MS, Peterson M, Miller J.
Cell. 1993 Jul 30;74(2):257-68.
PMID 8343954
 
The biosynthetic pathway of MHC class II but not class I molecules intersects the endocytic route.
Neefjes JJ, Stollorz V, Peters PJ, Geuze HJ, Ploegh HL.
Cell. 1990 Apr 6;61(1):171-83.
PMID 2156628
 
Proteolysis of the class II-associated invariant chain generates a peptide binding site in intracellular HLA-DR molecules.
Roche PA, Cresswell P.
Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3150-4.
PMID 2014234
 
Formation of a nine-subunit complex by HLA class II glycoproteins and the invariant chain.
Roche PA, Marks MS, Cresswell P.
Nature. 1991 Dec 5;354(6352):392-4.
PMID 1956401
 
Perivascular clusters of dendritic cells provide critical survival signals to B cells in bone marrow niches.
Sapoznikov A, Pewzner-Jung Y, Kalchenko V, Krauthgamer R, Shachar I, Jung S.
Nat Immunol. 2008 Apr;9(4):388-95. doi: 10.1038/ni1571. Epub 2008 Mar 2.
PMID 18311142
 
The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain.
Schneppenheim J, Dressel R, Huttl S, Lullmann-Rauch R, Engelke M, Dittmann K, Wienands J, Eskelinen EL, Hermans-Borgmeyer I, Fluhrer R, Saftig P, Schroder B.
J Exp Med. 2013 Jan 14;210(1):41-58. doi: 10.1084/jem.20121069. Epub 2012 Dec 24.
PMID 23267015
 
Requirement for invariant chain in B cell maturation and function.
Shachar I, Flavell RA.
Science. 1996 Oct 4;274(5284):106-8.
PMID 8810244
 
The secret second life of an innocent chaperone: the story of CD74 and B cell/chronic lymphocytic leukemia cell survival.
Shachar I, Haran M.
Leuk Lymphoma. 2011 Aug;52(8):1446-54. doi: 10.3109/10428194.2011.565437. Epub 2011 Mar 21. (REVIEW)
PMID 21417823
 
CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex.
Shi X, Leng L, Wang T, Wang W, Du X, Li J, McDonald C, Chen Z, Murphy JW, Lolis E, Noble P, Knudson W, Bucala R.
Immunity. 2006 Oct;25(4):595-606.
PMID 17045821
 
Cell-surface CD74 initiates a signaling cascade leading to cell proliferation and survival.
Starlets D, Gore Y, Binsky I, Haran M, Harpaz N, Shvidel L, Becker-Herman S, Berrebi A, Shachar I.
Blood. 2006 Jun 15;107(12):4807-16. Epub 2006 Feb 16.
PMID 16484589
 
CD74: a new candidate target for the immunotherapy of B-cell neoplasms.
Stein R, Mattes MJ, Cardillo TM, Hansen HJ, Chang CH, Burton J, Govindan S, Goldenberg DM.
Clin Cancer Res. 2007 Sep 15;13(18 Pt 2):5556s-5563s. (REVIEW)
PMID 17875789
 
Multiple roles of the invariant chain in MHC class II function.
Stumptner-Cuvelette P, Benaroch P.
Biochim Biophys Acta. 2002 Jan 30;1542(1-3):1-13. (REVIEW)
PMID 11853874
 
Update on activities at the Universal Protein Resource (UniProt) in 2013.
UniProt Consortium.
Nucleic Acids Res. 2013 Jan;41(Database issue):D43-7. doi: 10.1093/nar/gks1068. Epub 2012 Nov 17.
PMID 23161681
 
HIV-1 glycoprotein 41 ectodomain induces activation of the CD74 protein-mediated extracellular signal-regulated kinase/mitogen-activated protein kinase pathway to enhance viral infection.
Zhou C, Lu L, Tan S, Jiang S, Chen YH.
J Biol Chem. 2011 Dec 30;286(52):44869-77. doi: 10.1074/jbc.M111.267393. Epub 2011 Oct 28.
PMID 22039051
 

Citation

This paper should be referenced as such :
N Gil-Yarom, Herman S Becker, I Shachar
CD74 (CD74 molecule, major histocompatibility complex, class II invariant chain)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(12):879-885.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CD74ID45843ch5q33.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  Lung: Translocations in Adenocarcinoma
Lung: Translocations in Squamous Cell Carcinoma


External links

Nomenclature
HGNC (Hugo)CD74   1697
Cards
AtlasCD74ID45843ch5q33
Entrez_Gene (NCBI)CD74  972  CD74 molecule
AliasesDHLAG; HLADG; II; Ia-GAMMA
GeneCards (Weizmann)CD74
Ensembl hg19 (Hinxton)ENSG00000019582 [Gene_View]  chr5:149781200-149792499 [Contig_View]  CD74 [Vega]
Ensembl hg38 (Hinxton)ENSG00000019582 [Gene_View]  chr5:149781200-149792499 [Contig_View]  CD74 [Vega]
ICGC DataPortalENSG00000019582
TCGA cBioPortalCD74
AceView (NCBI)CD74
Genatlas (Paris)CD74
WikiGenes972
SOURCE (Princeton)CD74
Genetics Home Reference (NIH)CD74
Genomic and cartography
GoldenPath hg19 (UCSC)CD74  -     chr5:149781200-149792499 -  5q32   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)CD74  -     5q32   [Description]    (hg38-Dec_2013)
EnsemblCD74 - 5q32 [CytoView hg19]  CD74 - 5q32 [CytoView hg38]
Mapping of homologs : NCBICD74 [Mapview hg19]  CD74 [Mapview hg38]
OMIM142790   
Gene and transcription
Genbank (Entrez)AK292076 AK297889 AK300669 AK308929 BC018726
RefSeq transcript (Entrez)NM_001025158 NM_001025159 NM_004355
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CD74
Cluster EST : UnigeneHs.436568 [ NCBI ]
CGAP (NCI)Hs.436568
Alternative Splicing GalleryENSG00000019582
Gene ExpressionCD74 [ NCBI-GEO ]   CD74 [ EBI - ARRAY_EXPRESS ]   CD74 [ SEEK ]   CD74 [ MEM ]
Gene Expression Viewer (FireBrowse)CD74 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)972
GTEX Portal (Tissue expression)CD74
Protein : pattern, domain, 3D structure
UniProt/SwissProtP04233   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP04233  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP04233
Splice isoforms : SwissVarP04233
PhosPhoSitePlusP04233
Domaine pattern : Prosite (Expaxy)THYROGLOBULIN_1_1 (PS00484)    THYROGLOBULIN_1_2 (PS51162)   
Domains : Interpro (EBI)MHC_II-assoc_invar/CLIP_MHC-bd    MHC_II-assoc_invar_chain    MHC_II-assoc_invariant_trimer    Thyroglobulin_1   
Domain families : Pfam (Sanger)MHC2-interact (PF09307)    MHCassoc_trimer (PF08831)    Thyroglobulin_1 (PF00086)   
Domain families : Pfam (NCBI)pfam09307    pfam08831    pfam00086   
Domain families : Smart (EMBL)TY (SM00211)  
Conserved Domain (NCBI)CD74
DMDM Disease mutations972
Blocks (Seattle)CD74
PDB (SRS)1A6A    1ICF    1IIE    1L3H    1MUJ    3PDO    3PGC    3PGD    3QXA    3QXD    4AEN    4AH2    4X5W   
PDB (PDBSum)1A6A    1ICF    1IIE    1L3H    1MUJ    3PDO    3PGC    3PGD    3QXA    3QXD    4AEN    4AH2    4X5W   
PDB (IMB)1A6A    1ICF    1IIE    1L3H    1MUJ    3PDO    3PGC    3PGD    3QXA    3QXD    4AEN    4AH2    4X5W   
PDB (RSDB)1A6A    1ICF    1IIE    1L3H    1MUJ    3PDO    3PGC    3PGD    3QXA    3QXD    4AEN    4AH2    4X5W   
Structural Biology KnowledgeBase1A6A    1ICF    1IIE    1L3H    1MUJ    3PDO    3PGC    3PGD    3QXA    3QXD    4AEN    4AH2    4X5W   
SCOP (Structural Classification of Proteins)1A6A    1ICF    1IIE    1L3H    1MUJ    3PDO    3PGC    3PGD    3QXA    3QXD    4AEN    4AH2    4X5W   
CATH (Classification of proteins structures)1A6A    1ICF    1IIE    1L3H    1MUJ    3PDO    3PGC    3PGD    3QXA    3QXD    4AEN    4AH2    4X5W   
SuperfamilyP04233
Human Protein AtlasENSG00000019582
Peptide AtlasP04233
HPRD00825
IPIIPI00022933   IPI00217775   IPI00607573   IPI00982274   IPI00982493   IPI00977613   IPI00978259   IPI00979189   
Protein Interaction databases
DIP (DOE-UCLA)P04233
IntAct (EBI)P04233
FunCoupENSG00000019582
BioGRIDCD74
STRING (EMBL)CD74
ZODIACCD74
Ontologies - Pathways
QuickGOP04233
Ontology : AmiGOGolgi membrane  activation of MAPK activity  prostaglandin biosynthetic process  beta-amyloid binding  positive regulation of cytokine-mediated signaling pathway  positive regulation of dendritic cell antigen processing and presentation  negative regulation of peptide secretion  positive regulation of type 2 immune response  negative regulation of mature B cell apoptotic process  cytokine receptor activity  protein binding  intracellular  lysosomal membrane  multivesicular body  vacuole  plasma membrane  protein complex assembly  intracellular protein transport  defense response  signal transduction  cell proliferation  external side of plasma membrane  cell surface  ER to Golgi transport vesicle membrane  membrane  integral component of membrane  immunoglobulin mediated immune response  antigen processing and presentation of endogenous antigen  antigen processing and presentation of exogenous peptide antigen via MHC class II  cytokine binding  MHC class II protein complex binding  transport vesicle membrane  endocytic vesicle membrane  clathrin-coated endocytic vesicle membrane  positive regulation of B cell proliferation  trans-Golgi network membrane  macrophage migration inhibitory factor signaling pathway  macrophage migration inhibitory factor receptor complex  NOS2-CD74 complex  macrophage migration inhibitory factor binding  MHC class II protein binding  MHC class II protein binding  MHC class II protein complex  MHC class II protein binding, via antigen binding groove  identical protein binding  regulation of macrophage activation  negative regulation of apoptotic process  lysosomal lumen  negative regulation of DNA damage response, signal transduction by p53 class mediator  protein binding involved in protein folding  T cell selection  positive thymic T cell selection  negative thymic T cell selection  negative regulation of T cell differentiation  positive regulation of T cell differentiation  positive regulation of fibroblast proliferation  positive regulation of peptidyl-tyrosine phosphorylation  leukocyte migration  nitric-oxide synthase binding  chaperone mediated protein folding requiring cofactor  positive regulation of macrophage cytokine production  extracellular exosome  positive regulation of ERK1 and ERK2 cascade  positive regulation of ERK1 and ERK2 cascade  integral component of lumenal side of endoplasmic reticulum membrane  positive regulation of neutrophil chemotaxis  negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  positive regulation of chemokine (C-X-C motif) ligand 2 production  
Ontology : EGO-EBIGolgi membrane  activation of MAPK activity  prostaglandin biosynthetic process  beta-amyloid binding  positive regulation of cytokine-mediated signaling pathway  positive regulation of dendritic cell antigen processing and presentation  negative regulation of peptide secretion  positive regulation of type 2 immune response  negative regulation of mature B cell apoptotic process  cytokine receptor activity  protein binding  intracellular  lysosomal membrane  multivesicular body  vacuole  plasma membrane  protein complex assembly  intracellular protein transport  defense response  signal transduction  cell proliferation  external side of plasma membrane  cell surface  ER to Golgi transport vesicle membrane  membrane  integral component of membrane  immunoglobulin mediated immune response  antigen processing and presentation of endogenous antigen  antigen processing and presentation of exogenous peptide antigen via MHC class II  cytokine binding  MHC class II protein complex binding  transport vesicle membrane  endocytic vesicle membrane  clathrin-coated endocytic vesicle membrane  positive regulation of B cell proliferation  trans-Golgi network membrane  macrophage migration inhibitory factor signaling pathway  macrophage migration inhibitory factor receptor complex  NOS2-CD74 complex  macrophage migration inhibitory factor binding  MHC class II protein binding  MHC class II protein binding  MHC class II protein complex  MHC class II protein binding, via antigen binding groove  identical protein binding  regulation of macrophage activation  negative regulation of apoptotic process  lysosomal lumen  negative regulation of DNA damage response, signal transduction by p53 class mediator  protein binding involved in protein folding  T cell selection  positive thymic T cell selection  negative thymic T cell selection  negative regulation of T cell differentiation  positive regulation of T cell differentiation  positive regulation of fibroblast proliferation  positive regulation of peptidyl-tyrosine phosphorylation  leukocyte migration  nitric-oxide synthase binding  chaperone mediated protein folding requiring cofactor  positive regulation of macrophage cytokine production  extracellular exosome  positive regulation of ERK1 and ERK2 cascade  positive regulation of ERK1 and ERK2 cascade  integral component of lumenal side of endoplasmic reticulum membrane  positive regulation of neutrophil chemotaxis  negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  positive regulation of chemokine (C-X-C motif) ligand 2 production  
Pathways : BIOCARTAAntigen Processing and Presentation [Genes]   
Pathways : KEGGAntigen processing and presentation    Tuberculosis    Herpes simplex infection   
REACTOMEP04233 [protein]
REACTOME PathwaysR-HSA-2132295 [pathway]
NDEx NetworkCD74
Atlas of Cancer Signalling NetworkCD74
Wikipedia pathwaysCD74
Orthology - Evolution
OrthoDB972
GeneTree (enSembl)ENSG00000019582
Phylogenetic Trees/Animal Genes : TreeFamCD74
HOVERGENP04233
HOGENOMP04233
Homologs : HomoloGeneCD74
Homology/Alignments : Family Browser (UCSC)CD74
Gene fusions - Rearrangements
Fusion : MitelmanCD74/MBD6 [5q32/12q13.3]  
Fusion : MitelmanCD74/ROS1 [5q32/6q22.1]  [t(5;6)(q33;q22)]  
Fusion : MitelmanROS1/CD74 [6q22.1/5q32]  [t(5;6)(q33;q22)]  
Fusion : COSMICCD74 [5q32]  -  NRG1 [8p12]  [fusion_1635]  [fusion_1636]  [fusion_1665]  [fusion_1666]  
Fusion : COSMICCD74 [5q32]  -  ROS1 [6q22.1]  [fusion_1200]  [fusion_1201]  [fusion_1202]  [fusion_1203]  [fusion_1478]  [fusion_1619]  
Fusion : TICdbCD74 [5q32]  -  ROS1 [6q22.1]
Fusion Cancer (Beijing)CD74 [5q32]  -  ROS1 [6q22.1]  [FUSC003425]  [FUSC003425]
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCD74 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CD74
dbVarCD74
ClinVarCD74
1000_GenomesCD74 
Exome Variant ServerCD74
ExAC (Exome Aggregation Consortium)CD74 (select the gene name)
Genetic variants : HAPMAP972
Genomic Variants (DGV)CD74 [DGVbeta]
DECIPHER (Syndromes)5:149781200-149792499  ENSG00000019582
CONAN: Copy Number AnalysisCD74 
Mutations
ICGC Data PortalCD74 
TCGA Data PortalCD74 
Broad Tumor PortalCD74
OASIS PortalCD74 [ Somatic mutations - Copy number]
Cancer Gene: CensusCD74 
Somatic Mutations in Cancer : COSMICCD74  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDCD74
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch CD74
DgiDB (Drug Gene Interaction Database)CD74
DoCM (Curated mutations)CD74 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CD74 (select a term)
intoGenCD74
NCG5 (London)CD74
Cancer3DCD74(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM142790   
Orphanet
MedgenCD74
Genetic Testing Registry CD74
NextProtP04233 [Medical]
TSGene972
GENETestsCD74
Huge Navigator CD74 [HugePedia]
snp3D : Map Gene to Disease972
BioCentury BCIQCD74
ClinGenCD74
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD972
Chemical/Pharm GKB GenePA26236
Clinical trialCD74
Miscellaneous
canSAR (ICR)CD74 (select the gene name)
Probes
Litterature
PubMed141 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCD74
EVEXCD74
GoPubMedCD74
iHOPCD74
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Sat Jan 21 16:33:35 CET 2017

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.