The human plasma membrane sialidase NEU3 is a key enzyme in the catabolism of 
membrane gangliosides, is crucial in the regulation of cell surface processes, 
and has been demonstrated to be significantly up-regulated in renal cell 
carcinomas (RCCs). In this report, we show that NEU3 regulates β1 integrin 
trafficking in RCC cells by controlling β1 integrin recycling to the plasma 
membrane and controlling activation of the epidermal growth factor receptor 
(EGFR) and focal adhesion kinase (FAK)/protein kinase B (AKT) signaling. NEU3 
silencing in RCC cells increased the membrane ganglioside content, in particular 
the GD1a content, and changed the expression of key regulators of the integrin 
recycling pathway. In addition, NEU3 silencing up-regulated the Ras-related 
protein RAB25, which directs internalized integrins to lysosomes, and 
down-regulated the chloride intracellular channel protein 3 (CLIC3), which 
induces the recycling of internalized integrins to the plasma membrane. In this 
manner, NEU3 silencing enhanced the caveolar endocytosis of β1 integrin, blocked 
its recycling and reduced its levels at the plasma membrane, and, consequently, 
inhibited EGFR and FAK/AKT. These events had the following effects on the 
behavior of RCC cells: they (a) decreased drug resistance mediated by the block 
of autophagy and the induction of apoptosis; (b) decreased metastatic potential 
mediated by down-regulation of the metalloproteinases MMP1 and MMP7; and (c) 
decreased adhesion to collagen and fibronectin. Therefore, our data identify 
NEU3 as a key regulator of the β1 integrin-recycling pathway and FAK/AKT 
signaling and demonstrate its crucial role in RCC malignancy.