Septins are a family of cytoskeletal GTP-binding proteins that assemble into 
membrane-associated hetero-oligomers and organize scaffolds for recruitment of 
cytosolic proteins or stabilization of membrane proteins. Septins have been 
implicated in a diverse range of cancers, including gastric cancer, but the 
underlying mechanisms remain unclear. The hypothesis tested here is that septins 
contribute to cancer by stabilizing the receptor tyrosine kinase ErbB2, an 
important target for cancer treatment. Septins and ErbB2 were highly 
over-expressed in gastric cancer cells. Immunoprecipitation followed by MS 
analysis identified ErbB2 as a septin-interacting protein. Knockdown of septin-2 
or cell exposure to forchlorfenuron (FCF), a well-established inhibitor of 
septin oligomerization, decreased surface and total levels of ErbB2. These 
treatments had no effect on epidermal growth factor receptor (EGFR), emphasizing 
the specificity and functionality of the septin-ErbB2 interaction. The level of 
ubiquitylated ErbB2 at the plasma membrane was elevated in cells treated with 
FCF, which was accompanied by a decrease in co-localization of ErbB2 with 
septins at the membrane. Cathepsin B inhibitor, but not bafilomycin or 
lactacystin, prevented FCF-induced decrease in total ErbB2 by increasing 
accumulation of ubiquitylated ErbB2 in lysosomes. Therefore, septins protect 
ErbB2 from ubiquitylation, endocytosis and lysosomal degradation. The 
FCF-induced degradation pathway is distinct from and additive with the 
degradation induced by inhibiting ErbB2 chaperone Hsp90. These results identify 
septins as novel regulators of ErbB2 expression that contribute to the 
remarkable stabilization of the receptor at the plasma membrane of cancer cells 
and may provide a basis for the development of new ErbB2-targeting anti-cancer 
therapies.