Abstract
BackgroundThe cell adhesion molecule transmembrane and immunoglobulin (Ig) domain containing1 (TMIGD1) is a novel tumor suppressor that plays important roles in regulating cell–cell adhesion, cell proliferation and cell cycle. However, the mechanisms of TMIGD1 signaling are not yet fully elucidated.ResultsTMIGD1 binds to the ERM family proteins moesin and ezrin, and an evolutionarily conserved RRKK motif on the carboxyl terminus of TMIGD1 mediates the interaction of TMIGD1 with the N-terminal ERM domains of moesin and ezrin. TMIGD1 governs the apical localization of moesin and ezrin, as the loss of TMIGD1 in mice altered apical localization of moesin and ezrin in epithelial cells. In cell culture, TMIGD1 inhibited moesin-induced filopodia-like protrusions and cell migration. More importantly, TMIGD1 stimulated the Lysine (K40) acetylation of α-tubulin and promoted mitotic spindle organization and CRISPR/Cas9-mediated knockout of moesin impaired the TMIGD1-mediated acetylation of α-tubulin and filamentous (F)-actin organization.ConclusionsTMIGD1 binds to moesin and ezrin, and regulates their cellular localization. Moesin plays critical roles in TMIGD1-dependent acetylation of α-tubulin, mitotic spindle organization and cell migration. Our findings offer a molecular framework for understanding the complex functional interplay between TMIGD1 and the ERM family proteins in the regulation of cell adhesion and mitotic spindle assembly, and have wide-ranging implications in physiological and pathological processes such as cancer progression.
Highlights
The cell adhesion molecule transmembrane and immunoglobulin (Ig) domain containing1 (TMIGD1) is a novel tumor suppressor that plays important roles in regulating cell–cell adhesion, cell proliferation and cell cycle
We further validated the binding of TMIGD1 with moesin in HEK293 cells ectopically expressing moesin-GFP via this same GST-TMIGD1 pull-down assay; moesin-GFP was selectively pulled-down with GST-TMIGD1 (Fig. 1C)
Our analysis demonstrated that TMIGD1 mRNA is downregulated in all the major kidney cancer types including, kidney clear cell renal cell carcinoma (KIRC), kidney papillary renal cell carcinoma (KIRP) and chromophobe renal cell carcinoma (KICH) (Additional file 1: Figure S4A)
Summary
The cell adhesion molecule transmembrane and immunoglobulin (Ig) domain containing (TMIGD1) is a novel tumor suppressor that plays important roles in regulating cell–cell adhesion, cell proliferation and cell cycle. Altered cell–cell adhesion and disruption of apico-basal polarity are common features of all carcinomas [14, 39] Tumor suppressor genes such as VHL and APC that are frequently inactivated in human renal and colon cancers, are key regulators of cell adhesion and polarity[13, 23]. First discovered as a regulator of cell–cell adhesion and cell morphology, the cell adhesion molecule transmembrane and immunoglobulin (Ig) domain containing-1 (TMIGD1) is predominantly expressed in kidney and intestinal epithelial cells and protects renal epithelial cells from oxidative cell injury, promoting cell survival [2]. Re-expression of TMIGD1 in renal and colon cancer cell lines inhibits cell proliferation and induces G2/M cell cycle checkpoint arrest [10, Rahimi et al J Biomed Sci (2021) 28:61
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