TMIGD1 Is a Novel Adhesion Molecule That Protects Epithelial Cells from Oxidative Cell Injury

Arafa, E.I.; Bondzie, Philip A.; Rezazadeh, Kobra; Meyer, Rosana D.; Hartsough, Edward J.; Henderson, Joel M.; Schwartz, John H.; Chitalia, Vipul C.

doi:10.1016/j.ajpath.2015.06.006

Cited by 36 publications

(81 citation statements)

References 43 publications

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“…3a). It should be noted that similar differences in predicted size versus actual size have been observed previously for both TMIGD1 and TMIGD2, due to posttranslational modifications such as N -glycosylation1923. We then performed sphere-formation assays using SJSA-1, KHOS/NP and MG63 cells following overexpression of TMIGD3 i1, TMIGD3 i3 or A3AR.…”

Section: Resultsmentioning

confidence: 52%

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Genome-wide RNAi screening identifies TMIGD3 isoform1 as a suppressor of NF-κB and osteosarcoma progression

et al. 2016

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The ability of cancer cells to survive and grow in anchorage- and serum-independent conditions is well correlated with their aggressiveness. Here, using a human whole-genome shRNA library, we identify TMIGD3 isoform1 (i1) as a factor that suppresses this ability in osteosarcoma (OS) cells, mainly by inhibiting NF-κB activity. Knockdown of TMIGD3 increases proliferation, tumour formation and metastasis of OS cells. Overexpression of TMIGD3 isoform1 (i1), but not isoform3 (i3) which shares a common C-terminal region, suppresses these malignant properties. Adenosine A3 receptor (A3AR) having an identical N-terminal region shows similar biological profiles to TMIGD3 i1. Protein expression of TMIGD3 and A3AR is lower in human OS tissues than normal tissues. Mechanistically, TMIGD3 i1 and A3AR commonly inhibit the PKA−Akt−NF-κB axis. However, TMIGD3 i1 only partially rescues phenotypes induced by A3AR knockdown, suggesting the presence of distinct pathways. Our findings reveal an unappreciated role for TMIGD3 i1 as a suppressor of NF-κB activity and OS progression.

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Section: Resultsmentioning

confidence: 52%

“…TMIGD1 is implicated in cell differentiation and adhesion1920, whereas TMIGD2 is implicated in cancer immunosuppression as a receptor of HHLA2, a B7 family member21. However, there is no previous report about TMIGD3.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide RNAi screening identifies TMIGD3 isoform1 as a suppressor of NF-κB and osteosarcoma progression

et al. 2016

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“…Cell permeability and TEER assays were performed as described [9]. Briefly, PAE cells expressing IGPR-1 or control vector were seeded on tissue culture polycarbonate membrane filters coated with collagen I (pore size, 3.0 mm) in 24-well Transwell plates at a seeding density of 5,000 cells/well.…”

Section: Methodsmentioning

confidence: 99%

“…IGPR-1 expression is highly conserved in higher mammals, but no obvious homolog of IGPR-1 is found in mouse or rat [8]. However,, transmembrane and immunoglobulin domain-containing 1 (TMIGD1), which is the second member of the IGPR-1 family of proteins, is expressed both in humans and rodents [9]. Ectopic expression of IGPR-1 in porcine aortic endothelial (PAE) cells increased cell aggregation and deletion of the extracellular domain of IGPR-1 abrogated its adhesive function, thereby demonstrating that IGPR-1 acts as a putative CAM in endothelial cells [8].…”

Section: Introductionmentioning

confidence: 99%

IGPR-1 Is Required for Endothelial Cell–Cell Adhesion and Barrier Function

Wang

Meyer

Bondzie

et al. 2016

Journal of Molecular Biology

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Endothelial cell barrier function plays a prevalent regulatory mechanism for the integrity and homeostasis of blood vessels and modulates angiogenesis and immune responses. Cell adhesion molecules (CAMs) play a central role in the barrier function of endothelial cells. Although immunoglobulin containing and proline-rich receptor-1(IGPR-1) was recently identified as a novel CAM expressed in endothelial cells, the molecular mechanisms underlying the function of IGPR-1 in endothelial cells remain uncharacterized. In this report, we investigated the role of IGPR-1 in endothelial cell barrier function and the molecular mechanism of its activation in endothelial cells. We demonstrate that IGPR-1 is localized to endothelial adherens junctions, and through trans-homophilic dimerization regulates endothelial cell-cell adhesion and barrier function. Trans-homophilic dimerization of IGPR-1 stimulates phosphorylation of serine 220 (Ser220), which is required for IGPR-1 to regulate endothelial barrier function and angiogenesis. Moreover, IGPR-1 chimera, which mimics the trans-homophilic dimerization of IGPR-1, induced a sustained phosphorylation of Ser220 upon stimulation with a ligand. Coordinated dimerization of IGPR-1 and its homophilic interaction modulates its adhesive function and Ser220 phosphorylation. This adhesive function of IGPR-1 contributes to the barrier function of endothelial cells.

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“…Transmembrane and immunoglobulin domain containing (TMIGD) family proteins are newly identified class of immunoglobulin (Ig) domain containing cell adhesion molecules (Ig-CAMs), which include TMIGD1, immunoglobulin and proline rich receptor-1 (IGPR-1) [10][11][12] and TMIGD3 13 , which also acts as a tumor suppressor 14 . Although originally described as a protector of renal epithelial cells from oxidative cell injury 15 , TMIGD1 is downregulated in human renal cancer and its re-expression in renal tumor cells inhibits cell proliferation, migration and tumor growth in mouse tumor xenograft 15 . More importantly, a recent whole genome sequencing of pre-invasive colorectal tumor revealed that expression of TMIGD1 is progressively lost in colon cancer 16 .…”

Section: Introductionmentioning

confidence: 99%

TMIGD1, a putative tumor suppressor, induces G2-M cell cycle checkpoint arrest in colon cancer cells

Koc

Amraei

et al. 2020

Preprint

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Colorectal cancer (CRC) is a leading non-familial cause of cancer mortality among men and women.Although various genetic and epigenetic mechanisms have been identified, the full molecular mechanisms deriving CRC tumorigenesis remains incompletely understood. In this study, we demonstrate that cell adhesion molecule transmembrane and immunoglobulin domain containing1 (TMIGD1) is highly expressed in mouse and human normal intestinal epithelial cells. We have developed TMIGD1 knockout mice and show that the loss of TMIGD1 in mice results in the development of adenomas in small intestine and colon. Additionally, the loss of TMIGD1 in mouse impaired intestinal epithelium brush border formation, junctional polarity and maturation. Mechanistically, TMIGD1 inhibits tumor cell proliferation, cell migration, arrests cell cycle at G2/M phase and induces expression of p 21CIP1 (cyclin-dependent kinase inhibitor 1), and p 27KIP1 (cyclin-dependent kinase inhibitor 1B) expression, key cell cycle inhibitor proteins involved in the regulation of the cell cycle. Moreover, we demonstrate that TMIGD1 is progressively downregulated in sporadic human CRC and correlates with poor overall survival. Our findings identify TMIGD1 as a novel tumor suppressor gene and provide insights into the pathogenesis of colorectal cancer and possibilities as a potential therapeutic target.

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TMIGD1 Is a Novel Adhesion Molecule That Protects Epithelial Cells from Oxidative Cell Injury

Cited by 36 publications

References 43 publications

Genome-wide RNAi screening identifies TMIGD3 isoform1 as a suppressor of NF-κB and osteosarcoma progression

Genome-wide RNAi screening identifies TMIGD3 isoform1 as a suppressor of NF-κB and osteosarcoma progression

IGPR-1 Is Required for Endothelial Cell–Cell Adhesion and Barrier Function

TMIGD1, a putative tumor suppressor, induces G2-M cell cycle checkpoint arrest in colon cancer cells

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