The GPI-anchored protein CD109 protects hematopoietic progenitor cells from undergoing erythroid differentiation induced by TGF-β

Tanabe, Minoru; Hosokawa, Kohei; Nguyễn, Mai Ánh; Nakagawa, Noboru; Maruyama, Kana; Tsuji, Noriaki; Urushihara, Ryota; Espinoza, Luis; El-Badry, Mahmoud; Mohiuddin, Md.; Katagiri, Takamasa; Ono, Masanori; Fujiwara, Hiroshi; Chonabayashi, Kazuhisa; Yoshida, Yoshinori; Yamazaki, Hirohito; Hirao, Atsushi; Nakao, Shinji

doi:10.1038/s41375-021-01463-3

Cited by 12 publications

(7 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous reports identified CD109 as an IL-6 receptor independent modulator for gp130 mediated STAT3 phosphorylation 9,16 , to interact with EGFR directly and thereby change its signaling modalities and expression 10,11,46 and to enhance the Hippo pathway associated signaling transducers Yap/Taz 15 . Among different physiological functions such as protection of stem cells from premature differentiation 4 , detrimental properties have been described mostly linked to tumor biology 47,48 . For some tumor entities, CD109 was suggested as novel clinical biomarker 19 and for LUAD patients CD109 was identified among a cluster of risk genes in patients with poor prognosis 49 .…”

Section: Discussionmentioning

confidence: 99%

“…Premature lymphocytes, CD4 + and CD8 + T-cells, endothelial and epithelial cells express CD109 endogenously 3 . Premature lymphocytes require CD109 to protect themselves from transforming growth factor β (TGFβ) induced maturation 4 . In detail, CD109 interacts with the TGFβ/TGFβ-receptor (TGFβR) complex and suppresses SMAD2/3 phosphorylation 5,6 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

CD109 drives pro-tumorigenic cell properties in human non-small cell lung cancer through interaction with desmoglein-2

Lückstädt,

Rathod,

Möbus

et al. 2024

Preprint

View full text Add to dashboard Cite

Cluster of differentiation 109 (CD109) is a glycosylphosphatidylinositol (GPI) anchored cell surface protein, expressed on epithelial and endothelial cells, CD4+ and CD8+ T-cells, and premature lymphocytes. CD109 interacts with different cell surface receptors and thereby modulates intracellular signaling pathways, which ultimately changes cellular functions. One well-studied example is the interaction of CD109 with the TGFβ/TGFβ-receptor complex at the cell surface. CD109 silences intracellular SMAD2/3 signaling and targets TGFβ/TGFβ-receptor to the endosomal/lysosomal compartment. In recent years, CD109 emerged as a tumor marker for different tumor entities and expression of CD109 could be linked to adverse outcome in patients. In this study, we show that silencing of CD109 in human non-small cell lung cancer (NSCLC) cells, returns these cells to an epithelial like growth phenotype. On the transcriptional level, we describe changes in cell-cell contact and epithelial-mesenchymal transition associated gene clusters. At the cell surface, we identify desmoglein-2 (DSG2) as a new interaction partner of CD109 and demonstrate CD109 dependent targeting of DSG2 to the apical cell surface, where it forms desmosomes between apical and basal cell poles. Both, CD109 and DSG2 are genetic risk factors, linked to reduced overall survival in lung adenocarcinoma patients (subtype of NSCLC). In this study, we show the expression of both proteins in the same tumor and suggest a new CD109-DSG2 axis in NSCLC patients that could present a targetable therapeutic option in the future.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD109 drives pro-tumorigenic cell properties in human non-small cell lung cancer through interaction with desmoglein-2

Lückstädt,

Rathod,

Möbus

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…CD109 has been reported to be a protein in GPI-APs, a TGF coreceptor, which plays a key role in inhibiting TGF-signal-mediated erythrocyte differentiation. The lack of CD109 expression may make PIGA-mutated HSPCs more sensitive to TGF-β, leading to easier differentiation of mutant erythroid progenitors into mature erythrocytes [ 26 ]. Studies have found that PNH clones have anti-apoptotic properties.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA FAM157C contributes to clonal proliferation in paroxysmal nocturnal hemoglobinuria

Wang

Liu

et al. 2023

Ann Hematol

View full text Add to dashboard Cite

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease of hematopoietic stem cells (HSCs). Long noncoding RNAs (lncRNAs) perform a wide range of biological functions, including the regulation of gene expression, cell differentiation, and proliferation, but their role in PNH remains unclear.CD59− and CD59+ granulocytes and monocytes from 35 PNH patients were sorted. High-throughput sequencing was analyzed in 5 PNH patients, and differentially expressed lncRNAs and mRNAs were identified. The mRNAs with fragments per kilobase of exon model per million mapped fragments (FPKM) > 10 in at least 3 patients were selected, and experiments were performed to identify their upstream regulatory lncRNAs. The expression of selected mRNAs and lncRNAs was verified by qRT‒PCR, and the correlation of these expression patterns with clinical data from other 30 PNH patients was analyzed. Then, the functions of the lncRNAs were studied in the PIGA-KO-THP-1 cell line.Transcription analysis revealed 742 upregulated and 1376 downregulated lncRNAs and 3276 upregulated and 213 downregulated mRNAs. After deep screening, 8 highly expressed mRNAs that were related to the NF-κB pathway were analyzed to determine coexpression patterns. LINC01002, FAM157C, CTD-2530H12.2, XLOC-064331 and XLOC-106677 were correlated with the 8 mRNAs. After measuring the expression of these molecules in 30 PNH patients by qRT‒PCR, lncRNA FAM157C was verified to be upregulated in the PNH clone, and its expression levels were positively correlated with the LDH levels and CD59− granulated and monocyte cell ratios. After knockdown of the FAM157C gene in the PIGA-KO-THP-1 cell line, we found that the cells were arrested in the G0/G1 phase and S phase, the apoptosis rate increased, and the cell proliferation decreased.LncRNA FAM157C was proven to promote PNH clone proliferation, and this is the first study to explore the role of lncRNAs in PNH.

show abstract

“…Indeed, TGF-b1 levels were increased in the BM MK, although compared with only one (Nlrp3 +/+ /Gp1ba-Cre KI/+ ) but not another (Nlrp3 A350V/+ /Gp1ba-Cre +/+ ) control (Figure 1K). It is also known that CD109, a TGFb coreceptor, downregulates TGF-b signaling in hematopoietic progenitors (18), and its modified expression could therefore mediate reduced maturation of the early precursors even in the absence or minimal changes in the levels of TGF-b itself. Different subtypes of MK have recently been described, including platelet-forming, immunoregulatory, niche-supporting, and endomitotic cells (19).…”

Section: Hyperactive Mk Nlrp3 Could Modulate Erythropoiesis Through T...mentioning

confidence: 99%

Megakaryocyte NLRP3 hyperactivation induces mild anemia and potentiates inflammatory response in mice

et al. 2023

View full text Add to dashboard Cite

BackgroundThe NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been described in both immune cells and platelets, but its role in the megakaryocyte (MK) lineage remains elusive.ObjectiveThe aim of this study was to explore the role of NLRP3 inflammasome in megakaryocytes and platelets.MethodsWe generated Nlrp3A350V/+/Gp1ba-CreKI/+ mice carrying a mutation genetically similar to the one observed in human Muckle–Wells syndrome, which leads to hyperactivity of NLRP3 specifically in MK and platelets.ResultsPlatelets from the mutant mice expressed elevated levels of both precursor and active form of caspase-1, suggesting hyperactivity of NLRP3 inflammasome. Nlrp3A350V/+/Gp1ba-CreKI/+ mice developed normally and had normal platelet counts. Expression of major platelet receptors, platelet aggregation, platelet deposition on collagen under shear, and deep vein thrombosis were unchanged. Nlrp3A350V/+/Gp1ba-CreKI/+ mice had mild anemia, reduced Ter119+ cells in the bone marrow, and splenomegaly. A mild increase in MK TGF-β1 might be involved in the anemic phenotype. Intraperitoneal injection of zymosan in Nlrp3A350V/+/Gp1ba-CreKI/+ mice induced increased neutrophil egression and elevated levels of a set of proinflammatory cytokines, alongside IL-10 and G-CSF, in the peritoneal fluid as compared with control animals.ConclusionMK/platelet NLRP3 inflammasome promotes the acute inflammatory response and its hyperactivation in mice leads to mild anemia and increased extramedullary erythropoiesis.

show abstract

The GPI-anchored protein CD109 protects hematopoietic progenitor cells from undergoing erythroid differentiation induced by TGF-β

Cited by 12 publications

References 43 publications

CD109 drives pro-tumorigenic cell properties in human non-small cell lung cancer through interaction with desmoglein-2

CD109 drives pro-tumorigenic cell properties in human non-small cell lung cancer through interaction with desmoglein-2

Long noncoding RNA FAM157C contributes to clonal proliferation in paroxysmal nocturnal hemoglobinuria

Megakaryocyte NLRP3 hyperactivation induces mild anemia and potentiates inflammatory response in mice

Contact Info

Product

Resources

About