CD109: a multifunctional GPI‐anchored protein with key roles in tumor progression and physiological homeostasis

Abstract

CD109 is a glycosylphosphatidylinositol‐anchored glycoprotein and a member of the α2‐macroglobulin/C3,C4,C5 family of thioester‐containing proteins first identified as being expressed on blood cells, including activated T cells and platelets, and a subset of CD34 + bone marrow cells containing megakaryocyte progenitors. Although CD109 carries the biallelic platelet‐specific alloantigen Gov, the physiological functions or roles of CD109 in human disease remain largely unknown. It was recently demonstrated that CD109 is expressed in many malignant tumors, including various squamous cell carcinomas and adenocarcinomas, and plays a role as a multifunctional coreceptor. CD109 reportedly associates with transforming growth factor (TGF)‐β receptors and negatively regulates TGF‐β signaling in keratinocytes. Additionally, CD109 is potentially related to signal transducer and activator of transcription‐3 signaling and aberrant cell proliferation. In this review, we describe recent evidence of CD109‐specific significance in malignant tumors shown in mouse models and human tissues. Furthermore, we discuss the physiological functions of CD109 in vitro and in vivo, including results of phenotype analyses of CD109‐deficient mice exhibiting epidermal hyperplasia and osteopenia.

CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF‐β signaling

“…Although we found a novel upregulatory function of CD109 on TGF‐β signaling, one potential limitation of our study is that we could not elucidate the relationship between this upregulating effect of CD109 on TGF‐β signaling in tumor stroma and the downregulating effect of CD109 on epithelial cells, which was previously reported 12,14,23,48,49 . At present, the mechanisms underlying the paradoxical and context‐dependent effects of TGF‐β are still unclear 13,22 …”

“…We, however, observed that STAT3 phosphorylation was enhanced in CD109‐deficient cells in the previous study 23 . These controversial results suggested that STAT3 phosphorylation was regulated by CD109 in a complicated manner depending on the cell and tissue contexts 22 . CD109 also played a role in EGF signaling in glioma cells, 32 which was often activated by mutant EGFR in lung adenocarcinoma 37 .…”

“…12,14,23,48,49 At present, the mechanisms underlying the paradoxical and context-dependent effects of TGF-β are still unclear. 13,22 Furthermore, CD109 could be a potential therapeutic target because of its expression on the cell surface, enabling anti-CD109 antibodies to bind target cells in vivo, and because CD109-deficient mice exhibited no critical abnormalities. 23,24 Further investigation is required to develop in vivo CD109-targeting treatments.…”

Elevation of CD109 promotes metastasis and drug resistance in lung cancer via activation of EGFR‐AKT‐mTOR signaling

“…Cluster of differentiation 109 (CD109) is a glycosylphosphatidylinositol (GPI)‐anchored protein which belongs to the α2‐macroglobulin/C3, C4, and C5 family. CD109 was found to be expressed by endothelial, platelet, and hematopoietic progenitor cells 5 . The physiological function of CD109 in normal cells remains unclear, but it was reported that CD109 is upregulated in a wide variety of malignancies including squamous cell carcinomas, 6 glioblastomas, 7 melanomas, 8 and breast carcinomas 9 .…”

Trojan Horse Treatment Based on Peg-Coated Extracellular Vesicles to Deliver Doxorubicin to Melanoma in Vitro and in Vivo

“…The presence of these membrane proteins (tetraspanins, integrins and other surface proteins) on the EV surface could explain their increased uptake by recipient cells, as shown by the uptake assay (Figure 3), but also their potential to alter the behavior of recipient cells via activation of signaling pathways. Among these proteins, CD109 is a glycosylphosphatidylinositol-anchored glycoprotein acting as a multifunctional receptor associated with aberrant cancer cell proliferation 49 , integrin subunit beta 1 (ITGB1) and integrin subunit alpha V (ITGAV) both bind CX3C chemokine, attracting leukocytes as well as guiding EVs towards distinct target tissues 50,51 , transferrin receptor (TFRC) is a membrane glycoprotein that facilitates the cellular uptake 52 , sortilin 1 (SORT1) is involved in exosome release and transfer 53 , insulin like growth factor 2 receptor (IGF2R) is a tumor suppressor and a positive regulator of T-cell coactivation, facilitating immune cell responses and tumor invasion 24 . Another identified protein, was the specific melanoma glycoprotein non-metastatic b (GPNMB) which is a prometastatic and immunosuppressive molecule, previously reported to be present on melanoma exosomes 54,55 .…”