Multiple roles of the invariant chain in MHC class II function

Stumptner-Cuvelette, Pamela; Benaroch, Philippe

doi:10.1016/s0167-4889(01)00166-5

Cited by 143 publications

(111 citation statements)

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“…The mechanism that generates this unusual staining pattern is unknown but may be related to the physiological localization of the CD74 protein that chaperones MHC class II through the intracellular membrane system. 23 Similarly, the plasma membranous accentuation of reactivity associated with EZR-ROS1 may reflect the subcellular distribution of ezrin protein that links the plasma membrane with the actin cytoskeleton. 24 These characteristic ROS1-staining patterns were not observed in the 78 rearrangement-negative ROS1-expressing cancers in our cohort and, thus, they may be viewed as a rearrangement-specific phenomenon that can be useful for screening.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical detection of ROS1 is useful for identifying ROS1 rearrangements in lung cancers

et al. 2014

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The recent discovery and characterization of an oncogenic ROS1 gene fusion in a subset of lung cancers has raised significant clinical interest because small molecule inhibitors may be effective to these tumors. As lung cancers with ROS1 rearrangements comprise only 1-3% of lung adenocarcinomas, patients with such tumors must be identified to gain optimal benefit from molecular therapy. Recently, immunohistochemical analyses using a novel anti-ROS1 rabbit monoclonal antibody (D4D6) have shown promise for accurate identification of ROS1-rearranged cancers. To validate this finding, we compared the immunostaining results of tissue microarrays (TMAs) containing 17 ROS1-rearranged and 253 ROS1-non-rearranged lung carcinomas. All 17 ROS1-rearranged cancers showed ROS1 immunoreactivity mostly in a diffuse and moderate-to-strong manner with an H-score range of 5-300 (median, 260). In contrast, 69% of ROS1-non-rearranged cancers lacked detectable immunoreactivity, whereas the remaining 31% showed reactivity mainly in a weak or focal manner. The H-score for the entire ROS1-non-rearranged group ranged from 0 to 240 (median, 0). The difference in H-score between the two cohorts was statistically significant, and the H-score cutoff (Z150) allowed optimal discrimination (94% sensitivity and 98% specificity). Similar but slightly less-specific performance was achieved using the extent of diffuse (Z75%) staining or Z2 þ staining intensity as cutoffs. CD74-ROS1 and EZR-ROS1 fusions were significantly associated with at least focal globular immunoreactivity and plasma membranous accentuation, respectively, and these patterns were specific to ROS1-rearranged cases. Although full-length ROS1 is expressed in some ROS1-non-rearranged cases, we showed that establishment of an optimal set of interpretative criteria makes ROS1 immunohistochemistry a valuable method to rapidly and accurately screen lung cancer patients for appropriate molecular therapy.

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Section: Discussionmentioning

confidence: 99%

Immunohistochemical detection of ROS1 is useful for identifying ROS1 rearrangements in lung cancers

et al. 2014

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“…Required for Its Intramembrane Cleavage CD74 undergoes several proteolytic events in the endocytic compartments, resulting in the removal of the bulk of the lumenal domain and formation of a membrane-bound truncated protein (Stumptner-Cuvelette and Benaroch, 2002). To determine whether processing of the CD74 extracytoplasmic domain in the endocytic compartments is required for its intramembrane proteolytic cleavage, we blocked the export of CD74 to these endocytic compartments and analyzed the release of CD74-ICD.…”

Section: Processing Of Cd74 In the Endocytic Compartments Ismentioning

confidence: 99%

“…Alternative initiation of translation and differential splicing of the transcription products generate two different isoforms in mice (p31 and p41; Stumptner-Cuvelette and Benaroch, 2002). The CD74 chain was thought to function mainly as an MHC class II chaperone, which promotes ER exit of MHC class II molecules, directs them to endocytic compartments, prevents peptide binding in the ER, and contributes to peptide editing in the MHC class II compartment (Stumptner-Cuvelette and Benaroch, 2002). However, in addition to its function as a chaperone molecule, CD74 was recently shown to have a role as an accessory signaling molecule.…”

Section: Introductionmentioning

confidence: 99%

CD74 Is a Member of the Regulated Intramembrane Proteolysis-processed Protein Family

Becker-Herman

Arie

Medvedovsky

et al. 2005

MBoC

115

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Quite a few regulatory proteins, including transcription factors, are normally maintained in a dormant state to be activated after internal or environmental cues. Recently, a novel strategy, requiring proteolytic cleavage, was described for the mobilization of dormant transcription factors. These transcription factors are initially synthesized in an inactive form, whereas "nesting" in integral membrane precursor proteins. After a cleavage event, these new active factors are released from the membrane and can migrate into the nucleus to drive regulated gene transcription. This mechanism, regulated intramembrane proteolysis (RIP), controls diverse biological processes in prokaryotes and eukaryotes in response to a variety of signals. The MHC class II chaperone, CD74 (invariant chain, Ii), was previously shown to function as a signaling molecule in several pathways. Recently, we demonstrated that after intramembranal cleavage, the CD74 cytosolic fragment (CD74-ICD) is released and induces activation of transcription mediated by the NF-B p65/RelA homodimer and the B-cell-enriched coactivator, TAF II 105. Here, we add CD74 to the growing family of RIP-processed proteins. Our studies show that CD74 ectodomain must be processed in the endocytic compartments to allow its intramembrane cleavage that liberates CD74 intracellular domain (CD74-ICD). We demonstrate that CD74-ICD translocates to the nucleus and induces the activation of the p65 member of NF-B in this compartment. INTRODUCTIONQuite a few regulatory proteins, including transcription factors, are normally maintained in a dormant state and are activated by internal or environmental cues. Recently, a novel strategy (regulated intramembrane proteolysis [RIP]), based on proteolytic cleavage, was discovered for the mobilization of dormant transcription factors. These transcription factors are synthesized initially as inactive, membranebound precursors. Once triggered, RIP proteins are cleaved within the plane of the membrane, and their cytosolic fragment migrates into the nucleus to drive transcription.In general, in most RIP cases reported, cleavage proceeds through a two-step sequential proteolytic process. The first step involves the cleavage of the extracytoplasmic segment to shorten the ectodomain to Ͻ30 aa. This seems to be a requirement for the second proteolytic event, which occurs at the transmembrane domain. The initial shedding prepares the substrate for the intramembrane proteolysis such that the transmembrane region becomes accessible to the second protease, which then releases the product from the lipid bilayer. The released cytosolic fragment then migrates into the nucleus. Intramembrane cleaving proteases (I-CLiPs) catalyze peptide bond hydrolysis in the plane of cellular membranes. These proteases are thought to mediate RIP (Brown et al., 2000), and the reactions they catalyze are, in most cases, part of highly controlled processes. The family of I-CLiPs is growing, and at present, three distinct protease families have been shown to catalyze intramem...

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“…Previous studies have shown that chronic lymphocytic leukemia (CLL) lymphocytes express relatively large amounts of mRNA for CD74, which is the cell-surface form of invariant chain (Ii), as compared with normal B cells (2,3). CD74 is a nonpolymorphic type II integral membrane protein, which was originally thought to function mainly as an MHC class II chaperone (4). However, CD74 recently was found to play an additional role as an accessory-signaling molecule.…”

mentioning

confidence: 99%

IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival

Binsky

Haran

Starlets

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

164

154

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Chronic lymphocytic leukemia (CLL) is a malignant disease of small mature lymphocytes. Previous studies have shown that CLL B lymphocytes express relatively large amounts of CD74 mRNA relative to normal B cells. In the present study, we analyzed the molecular mechanism regulated by CD74 in B-CLL cells. The results presented here show that activation of cell-surface CD74, expressed at high levels from an early stage of the disease by its natural ligand, macrophage migration-inhibition factor (MIF), initiates a signaling cascade that contributes to tumor progression. This pathway induces NF-B activation, resulting in the secretion of IL-8 which, in turn, promotes cell survival. Inhibition of this pathway leads to decreased cell survival. These findings could form the basis of unique therapeutic strategies aimed at blocking the CD74-induced, IL-8-dependent survival pathway.apoptosis ͉ invariant chain B cell chronic lymphocytic leukemia (B-CLL) is characterized by the progressive accumulation of CD5 ϩ B lymphocytes in peripheral blood, lymphoid organs, and bone marrow (1). The hallmark of the disease is decreased apoptosis, resulting in accumulation of these malignant cells. Previous studies have shown that chronic lymphocytic leukemia (CLL) lymphocytes express relatively large amounts of mRNA for CD74, which is the cell-surface form of invariant chain (Ii), as compared with normal B cells (2, 3). CD74 is a nonpolymorphic type II integral membrane protein, which was originally thought to function mainly as an MHC class II chaperone (4). However, CD74 recently was found to play an additional role as an accessory-signaling molecule. In macrophages, CD74 demonstrates high-affinity binding to the proinflammatory cytokine, macrophage migration-inhibitory factor (MIF). MIF binds to the extracellular domain of CD74; this complex is required for MIF-mediated MAPK activation and cell proliferation (5). Moreover, the bacterium Helicobacter pylori was shown to bind to CD74 on gastric epithelial cells and to stimulate IL-8 production (6).In a previous study, we showed that CD74 is involved directly in shaping the B cell repertoire (7, 8) by a pathway leading to the activation of transcription mediated by the NF-B p65/RelA homodimer and its coactivator, TAFII105 (9). NF-B activation is mediated by the cytosolic region of CD74 (CD74-ICD), which translocates to the cell nucleus (10). This signal is terminated by degradation of the active CD74-ICD fragment (11,12). Moreover, we demonstrated recently that CD74 stimulation with an agonistic CD74 antibody leads to NF-B activation, enabling entry of the stimulated B cells into the S phase, an increase in DNA synthesis, cell division, and augmented expression of members of the Bcl-2 protein family. Thus, these findings indicate that surface CD74 functions as a survival receptor (13).In the present study, we sought to determine whether CD74 functions as a survival receptor in B-CLL cells. Our results show that MIF-induced CD74 activation initiates a signaling cascade that results in secr...

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Multiple roles of the invariant chain in MHC class II function

Cited by 143 publications

References 149 publications

Immunohistochemical detection of ROS1 is useful for identifying ROS1 rearrangements in lung cancers

Immunohistochemical detection of ROS1 is useful for identifying ROS1 rearrangements in lung cancers

CD74 Is a Member of the Regulated Intramembrane Proteolysis-processed Protein Family

IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival

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