Colorectal Cancer (CRC) is one of the most common cancers worldwide. Although various genetic and environmental mechanisms have been identified, the full molecular mechanisms deriving CRC tumorigenesis remain largely unknown. Transmembrane and Immunoglobulin Domain Containing-1 (TMIGD1) is a newly identified candidate tumor suppressor that is mainly expressed in the kidneys and intestines. However, whether TMIGD1 is involved in the tumorigenesis of CRC is not currently known. The main objective of this project was to investigate the effects of the loss of TMIGD1 on intestinal morphology and cellular differentiation in wildtype and knockout mice. Our findings illustrate that the loss of TMIGD1 causes intestinal adenomas and disrupts intestinal brush border formation in mouse models. Furthermore, our research shows that the loss of TMIGD1 in mice affects cellular maturation and intestinal epithelium differentiation. We also demonstrate that TMIGD1 is downregulated in human CRC tissue. Taken together, our results reveal that the loss of TMIGD1 in mouse colonic epithelium results in impaired intestinal epithelium brush border formation, junctional polarity, and development of colonic adenoma. / 2021-06-04T00:00:00Z

Kidney disease has a high incidence across the globe and can be caused by acute and chronic injury. Current methods of treatment range from prevention and management with diet and extend to hemodialysis at End Stage Renal Disease (ESRD). Transmembrane Immunoglobulin Domain Containing-1 (TMIGD1) is mainly expressed in kidney and the intestines and is involved in cell-cell interaction of epithelial cells. This thesis investigated the potential role of TMIGD1 in the development of chronic kidney disease and tubular epithelial cell injury in CRISPR/Cas9-TMIGD1 transgenic mouse. Treatment of wild-type mice with adenine showed that TMIGD1 is downregulated in response to adenine-induced renal cell injury. CRISPR/Cas9-TMIGD1 -/+ mice treated with adenine displayed significantly increased tubular damage compared to wild-type mice. Additionally, expression of TMIGD1 was directly correlated with localization of C/EBPβ to nucleus, a transcription factor that is known to regulate expression of TMIGD1. In conclusion, the loss of TMIGD1 negatively impacts response to renal stress. / 2020-06-17T00:00:00Z

Dysregulation of protein expression, in particular expression of proto-oncogenes and tumor-suppressor genes whose function play key roles in cell growth, adhesion and migration, are hallmarks of human malignancies. Transmembrane and immunoglobulin-containing domain 1 (TMIGD1) was recently discovered as a cell adhesion molecule (CAM) that plays an important role in epithelial cell function by regulating epithelial cell polarity and adhesion. The extracellular domain of TMIGD1 contains two Ig domains that are involved in cell-cell interaction, followed by a transmembrane region and short cytoplasmic domain with potential to relay signal transduction. Our further investigation demonstrated TMIGD1 is downregulated in human colon cancer, suggesting a potentially important role for TMIGD1 in the regulation colorectal cancer. However, the molecular mechanisms of TMIGD1-mediated signal transduction, which could relay its function in epithelial cells, are not known. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, we have identified moesin as a possible TMIGD1 binding protein. Moesin, a member of the Ezrin/Radixin/Moesin (ERM) family of proteins, is upregulated in human tumors. Moesin stimulates cell migration, tumor invasion, adherence and modulates cytoskeletal actin assembly. Similar to other ERM family proteins, moesin contains an N-terminal FERM domain, which binds to transmembrane proteins, and a C-terminal C-ERMAD domain, which binds F-actin. The overall goal of this study was to determine the binding of moesin with TMIGD1 and the specific domain involved in mediating the binding of moesin with TMIGD1. Our study in vitro and in vivo binding assays demonstrate that moesin interacts with the cytoplasmic domain of TMIGD1 via its FERM domain. Moreover, we demonstrate TMIGD1 interaction with moesin inhibits phosphorylation of moesin, indicating that perhaps TMIGD1 inhibits tumor cell migration through inhibition of phosphorylation of moesin. Additionally, TMIGD1 alters cellular localization of moesin, suggesting that altered cellular localization by TMIGD1 could account for inhibition of phosphorylation of moesin. We propose that TMIGD1 sequesters moesin near the cell membrane, preventing its interaction with PIP2, which is required for its phosphorylation and hence inhibits moesin activation. Altogether, the data presented in this work identifies moesin as a key signaling component of TMIGD1. Moesin directly interacts with TMIGD1 via its FERM domain. Recruitment of moesin to TMIGD1 blocks phosphorylation of moesin, suggesting that TMIGD1 exerts its effect in tumor cells in part by inhibition of moesin activation. / 2018-07-11T00:00:00Z

Epithelial cells are unique for their ability to strongly adhere to one another and coordinate communication across an asymmetrical, polar plasma membrane. These properties are necessary for carrying out normal epithelial function, such as absorbing/secreting molecules, repairing wounds, lining organs, etc. Cadherins, claudins, and occludins are major players of epithelial cell adhesion and polarity. Previously, transmembrane immunoglobulin domain containing-1, TMIGD1, was identified as a novel cell adhesion molecule, whose expression is downregulated in human renal carcinomas. Re-expression of TMIGD1 in renal tumor cells resulted in altered cell morphology and inhibition of tumor growth. In this study, we examined the hypothesis that TMIGD1 activity is associated with epithelial cell polarity. We demonstrated that TMIGD1 regulates actin stress fibril formation. A 3-dimensional (3D) cell culture assay was developed to examine the role of TMIGD1 in cell morphology and polarity. Our results demonstrate that TMIGD1 regulates actin fibril formation in Madin-Darby Canine Kidney (MDCK) cells, as blocking TMIGD1 activity by blocking antibody inhibited actin fibril formation in 3D cell culture system. Moreover, ectopic expression of TMIGD1 in rectal carcinoma cells, (RKO) , significantly inhibited filopodia formation. Taken together, our data identifies TMIGD1 as a possible regulator of epithelial cell morphology and polarity. / 2020-07-03T00:00:00Z