Introduction: The loss of E-cadherin based cell-cell contacts and tumor cell migration to the vasculature and lymphatic system are hallmarks of metastasis of epithelial cancers. Type I gamma phosphatidylinositol phosphate kinase (PIPKIγ), an enzyme that generates phosphatidylinositol 4,5-bisphosphate (PI4,5P₂) a lipid messenger and precursor to many additional second messengers, was found to regulate E-cadherin cell-cell contacts and growth factor-stimulated directional cell migration, indicating that PIPKIγ regulates key steps in metastasis. Here, we assess the expression of PIPKIγ in breast cancers and have shown that expression correlated with disease progression and outcome. Methods: Using a tissue microarray, we analyzed 438 breast carcinomas for the levels of PIPKIγ and investigated the correlation of PIPKIγ expression with patient survival via Kaplan-Meier survival analysis. Moreover, via knockdown of the expression of PIPKIγ in cultured breast cancer cells with siRNA, the roles of PIPKIγ in breast cancer migration, invasion, and proliferation were examined. Results: Tissue microarray data shows that ~18% of the cohort immunostained showed high expression of PIPKIγ. The Kaplan-Meier survival analysis revealed a significant inverse correlation between strong PIPKIγ expression and overall patient survival. Expression of PIPKIγ correlated positively with epidermal growth factor receptor (EGFR) expression, which regulates breast cancer progression and metastasis. In cultured breast cancer cells, PIPKIγ is required for growth factor stimulated migration, invasion, and proliferation of cells. Conclusions: The results reveal a significant correlation between PIPKIγ expression and the progression of breast cancer. This is consistent with PIPKIγ 's role in breast cancer cell migration, invasion, and proliferation.

The capacity for cancer cells to metastasize to distant organs depends on their ability to execute the carefully choreographed processes of cell adhesion and migration. As most human cancers are of epithelial origin (carcinoma), the transcriptional downregulation of adherent/tight junction proteins (e.g., E-cadherin, Claudin and Occludin) with the concomitant gain of adhesive and migratory phenotypes has been extensively studied. Most research and reviews on cell adhesion and migration focus on the actin cytoskeleton and its reorganization. However, metastasizing cancer cells undergo the extensive reorganization of their cytoskeletal system, specifically in originating/nucleation sites of microtubules and their orientation (e.g., from non-centrosomal to centrosomal microtubule organizing centers). The precise mechanisms by which the spatial and temporal reorganization of microtubules are linked functionally with the acquisition of an adhesive and migratory phenotype as epithelial cells reversibly transition into mesenchymal cells during metastasis remains poorly understood. In this Special Issue of “Molecular Mechanisms Underlying Cell Adhesion and Migration”, we highlight cell adhesion and migration from the perspectives of microtubule cytoskeletal reorganization, cell polarity and phosphoinositide signaling.

Cytoplasmic phosphoinositides (PI) are critical regulators of the membrane–cytosol interface that control a myriad of cellular functions despite their low abundance among phospholipids. The metabolic cycle that generates different PI species is crucial to their regulatory role, controlling membrane dynamics, vesicular trafficking, signal transduction, and other key cellular events. The synthesis of phosphatidylinositol (3,4,5)-triphosphate (PI3,4,5P₃) in the cytoplamic PI3K/Akt pathway is central to the life and death of a cell. This review will focus on the emerging evidence that scaffold proteins regulate the PI3K/Akt pathway in distinct membrane structures in response to diverse stimuli, challenging the belief that the plasma membrane is the predominant site for PI3k/Akt signaling. In addition, we will discuss how PIs regulate the recruitment of specific scaffolding complexes to membrane structures to coordinate vesicle formation, fusion, and reformation during autophagy as well as a novel lysosome repair pathway.