Abstract
ErbB2 is an important member of the ErbB family, which activates growth and proliferation signaling pathways. ErbB2 is often overexpressed in various malignancies, especially in breast cancer, and is a common target for anti-cancer drugs. Breast cancer is currently one of the leading mortality causes in women, and acquired resistance to ErbB2-targeted therapies is a major obstacle in its treatment. Thus, understanding ErbB2-mediated signaling is crucial for further development of anti-cancer therapeutics and disease treatment. Previously, we have reported that the ErbB receptors interact with the major nucleolar protein nucleolin. In addition to its function in the nucleoli of cells, nucleolin participates in various cellular processes at the cytoplasm and cell-surface. Deregulated nucleolin is frequently overexpressed on the membrane of cancer cells. Here, we show that nucleolin increases colony formation and anchorage-independent growth of ErbB2-overexpressing cells. Importantly, this enhanced tumorigenicity also occurs in human ErbB2-positive breast cancer patients; namely, nucleolin overexpression in these patients is associated with reduced patient survival rates and increased disease-risk. ErbB2-nucleolin complexes are formed endogenously in both normal and cancer cells, and their effect on tumorigenicity is mediated through activation of ErbB2 signaling. Accordingly, nucleolin inhibition reduces cell viability and ErbB2 activation in ErbB2-positive cancer cells.
Highlights
The ErbB family of receptor tyrosine kinases (RTKs) mediates basic cellular processes, such as cell survival, proliferation and migration
Having demonstrated that nucleolin binds ErbB receptors, in the present study, we have characterized the interaction between nucleolin and ErbB2 and its oncogenic effects
ErbB2 and nucleolin physically interact in intact cells
Summary
The ErbB family of receptor tyrosine kinases (RTKs) mediates basic cellular processes, such as cell survival, proliferation and migration. This family includes four members: ErbB1 (EGFR), ErbB2 (HER2/neu), ErbB3 (HER3) and ErbB4 (HER4), which participate in signal transduction in response to extracellular stimuli [1]. Activation of these receptors occurs following ligand binding, which triggers receptor homo- or heterodimerization with other family members, leading to tyrosine phosphorylation of the cytoplasmic tail. Despite the fact that ErbB2 is an orphan receptor, it is one of the most active receptors of the family. It has an open conformation, with its dimerization loop constantly exposed, which facilitates the formation of an ErbB2 dimer with other adjacent ErbBs [2,3,4]
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