Abstract
Cell to cell adhesion is mediated by adhesion molecules present on the cell surface. Downregulation of molecules that form the adhesion complex is a characteristic of metastatic cancer cells. Downregulation of the N-myc down regulated gene1 (NDRG1) increases prostate and breast metastasis. The exact function of NDRG1 is not known. Here by using live cell confocal microscopy and in vitro reconstitution, we report that NDRG1 is involved in recycling the adhesion molecule E-cadherin thereby stabilizing it. Evidence is provided that NDRG1 recruits on recycling endosomes in the Trans Golgi network by binding to phosphotidylinositol 4-phosphate and interacts with membrane bound Rab4aGTPase. NDRG1 specifically interacts with constitutively active Rab4aQ67L mutant protein and not with GDP-bound Rab4aS22N mutant proving NDRG1 as a novel Rab4a effector. Transferrin recycling experiments reveals NDRG1 colocalizes with transferrin during the recycling phase. NDRG1 alters the kinetics of transferrin recycling in cells. NDRG1 knockdown cells show a delay in recycling transferrin, conversely NDRG1 overexpressing cells reveal an increase in rate of transferrin recycling. This novel finding of NDRG1 as a recycling protein involved with recycling of E-cadherin will aid in understanding NDRG1 role as a metastasis suppressor protein.
Highlights
Epithelial to mesenchymal transition is central to many physiological and pathological processes including embryogenesis, wound healing and metastasis [1]
The adherens junction in epithelial cells is characterized by the E-cadherin complex
In this report evidence is provided that N-myc down regulated gene1 (NDRG1) is a Rab4a effector protein that localizes to perinuclear recycling/sorting vesicles in the Trans Golgi network by binding to phophatidylinositol 4-phosphate and is involved in recycling of E-cadherin
Summary
Epithelial to mesenchymal transition is central to many physiological and pathological processes including embryogenesis, wound healing and metastasis [1]. In this report evidence is provided that NDRG1 is a Rab4a effector protein that localizes to perinuclear recycling/sorting vesicles in the Trans Golgi network by binding to phophatidylinositol 4-phosphate and is involved in recycling of E-cadherin. None of the proteins of the E-cadherin complex co-immunoprecipitated with flag-tagged NDRG1 in DU-145 and CWR22R prostate cancer cells, suggesting other mechanisms involving NDRG1 may play a role in the stability of E-cadherin (Figure 2D and data not shown).
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