Abstract
The multi-functional adaptor protein NEDD9/HEF1/Cas-L regulates cell motility, invasion and cell cycle progression, and plays key roles in cancer progression and metastasis. NEDD9 is localized to the centrosome and is required for activation of Aurora A kinase in mitosis. Here we demonstrate that the HECT-WW protein Smurf2 physically associates with NEDD9 and is required for the stability of NEDD9 protein. Smurf2 depletion results in a marked decrease in NEDD9 protein levels, by facilitating polyubiquitination and proteasomal degradation of NEDD9. Conversely, forced overexpression of Smurf2 results in upregulation of endogenous NEDD9 protein, confirming the role for Smurf2 in NEDD9 stability. Cells with Smurf2 depletion fail to activate Aurora A at the G2/M boundary, leading to a marked delay in mitotic entry. These observations suggest that the stable complex of Smurf2 and NEDD9 is required for timely entry into mitosis via Aurora A activation.
Highlights
Smurf2 (Smad ubiquitination regulatory factor 2) is a HECT-E3 ligase that negatively regulates Transforming growth factor (TGF-b) signaling [1]
Since Neural precursor cell expressed (NEDD9) plays diverse roles in focal adhesion and cell motility and in mitotic regulation, we further analyzed the potential interaction between Smurf2 and NEDD9
Our data do not exclude that this interaction could require other proteins, but these data do suggest that Smurf2 and NEDD9 are in complex with each other, most abundantly so during mitosis
Summary
Smurf (Smad ubiquitination regulatory factor 2) is a HECT-E3 ligase that negatively regulates TGF-b signaling [1]. In addition to its role in TGF-b signaling, Smurf functions in diverse biological pathways, including those controlling the cell cycle and cell polarity/cytoskeletal remodeling [5,6,7,8,9]. Previous work from our laboratory demonstrated that Smurf protein levels vary during the cell cycle, peaking during mitosis [6]. The localization of Smurf undergoes dynamic regulation. Smurf is at the centrosome from G1 through prophase, localizes to the spindle midzone during anaphase, and the midbody during cytokinesis [6]. The best-defined role of Smurf in mitosis involves its binding to and stabilization of Mad, which is required for the spindle assembly checkpoint [6]
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