Endomembrane control of cell polarity: Relevance to cancer

Abstract

The role of polarity in cancer is an emerging research area and loss of polarity is widely considered an important event in cancer. Among the polarity regulating molecules, the small GTPase Cdc42 was extensively studied. Most attention was given to Cdc42 signaling at the plasma membrane, but whether and how Cdc42 is regulated at endomembranes remained poorly understood. Moreover, whether the endomembrane pool of Cdc42 is of any relevance to cell polarity was unknown. In our recent work, we identified a complex between the Golgi matrix protein GM130 and RasGRF and showed that it is responsible for regulating the Golgi pool of Cdc42, but had no effect on the plasma membrane pool of Cdc42. Depletion of GM130 disrupted apico-basal polarity as well as front-rear polarity, indicating that the spatial pool of Cdc42 is functionally relevant. The biomedical relevance of this finding was supported by the observation than GM130 is progressively lost in colorectal cancer. These findings support a role of the endomembrane pool of Cdc42 in cell polarity and point to a potential role of alterations of this pool in cancer.

The Physiological Functions of the Golgin Vesicle Tethering Proteins

“…It should be noted that only a single patient with this disorder has been identified, and although the mutation in this patient resulted in a loss of GM130 protein, the identification of additional patients will be required to establish this condition as a GM130-dependent disorder. Reduced expression of GM130 has also been implicated in tumorigenesis (Baschieri et al, 2014; Baschieri and Farhan, 2015). GM130 levels are reduced in breast cancer, and depletion of GM130 in cancer cells increases cell migration, which may be relevant for the human disease.…”

Activity and Trafficking of Copper-Transporting ATPases in Tumor Development and Defense against Platinum-Based Drugs

“…The process of tumor development involves a remarkable rearrangement in the functions of virtually all cellular organelles. This includes the Golgi apparatus, which holds a strategic position at the crossroads of the main membrane trafficking pathways and harbors molecular platforms operating in intracellular signaling, cytoskeleton organization, and protein quality control mechanisms [1,2]. In malignant cells, the Golgi plays a significant role in the processing and focalized delivery of matrix digesting proteins that are required for invasion [3,4].…”

“…In malignant cells, the Golgi plays a significant role in the processing and focalized delivery of matrix digesting proteins that are required for invasion [3,4]. The Golgi also integrates membrane trafficking events with reorganization of cytoskeletal and cellular cues to modify the environment of the tumor cell and, hence, to promote its ability to conquer surrounding healthy tissue [2,5,6]. Finally, Golgi membranes host a variety of signaling molecules that control several checkpoints for mitotic progression, while in tumor cells the structural and molecular reorganization of the Golgi compartment frequently leads to a failure of these checkpoints and, as a result, to uncontrolled proliferation [7].…”

Alterations of Golgi Structural Proteins and Glycosylation Defects in Cancer

“…Loss of GM130 expression is frequently observed in colorectal and breast cancer patients. Silencing GM130 reduces Cdc42 activity on the Golgi and down-regulates E-cadherin expression, indicating a loss in cell polarity and epithelial identity ( Baschieri et al, 2014 ; Baschieri and Farhan, 2015 ). GM130 deletion is also associated with increased migration and invasion of breast cancer cells ( Baschieri et al, 2015 ).…”