Abstract
Cyclin-dependent kinase 5 (Cdk5) is predominantly expressed in neuron and plays an important role in neuronal physiology. Increasing evidence also indicates that Cdk5 may contribute to malignant progression of some types of cancers; however, the underlying mechanism remains elusive. In this study, we found that Cdk5 directly phosphorylated the actin-binding protein adducin-1 (ADD1) at T724 in vitro and in intact cells. The capability of the phosphomimetic T724D mutant to bind to actin filaments was lower than that of wild type ADD1 and the T724A mutant. Cdk5 co-localized with ADD1 at the lamellipodia upon epidermal growth factor (EGF) stimulation. The increased lamellipodia formation and cell migration of human breast cancer cells MDA-MB-231 by EGF were accompanied by Cdk5 activation and increased phosphorylation of ADD1 at T724. Depletion of Cdk5 in MDA-MB-231 cells abrogated the effects of EGF on ADD1 T724 phosphorylation, lamellipodia formation, and cell migration. Likewise, depletion of ADD1 suppressed the effects of EGF on lamellipodia formation, cell migration, and invasion, all of which were restored by FLAG-ADD1 WT and the T724D mutant, but not the T724A mutant. Together, our results suggest that phosphorylation of ADD1 at T724 by Cdk5 is important for EGF-induced cell migration and invasion.
Highlights
Cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/threonine kinase, is an atypical cyclin-dependent kinase that has long been considered as a neuronal kinase[1]
The increased expression of ADD1 was correlated with increased phosphorylation at T724 and S726. These results suggest that activation of Cdk[5] and protein kinase Cδ (PKCδ) and phosphorylation of ADD1 at T724 and S726 may be correlated with the metastatic potential of cancer cells
We identified ADD1 as a novel substrate of Cdk[5] (Fig. 1) and demonstrated that ADD1 phosphorylation at T724 by Cdk[5] is important for epidermal growth factor (EGF)-induced cell migration and invasion in MDA-MB-231 breast cancer cells (Fig. 6)
Summary
Cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/threonine kinase, is an atypical cyclin-dependent kinase that has long been considered as a neuronal kinase[1]. Its kinase activity is important for the migration and metastatic invasion of some forms of cancers, including breast[4], lung[5], melanoma[6], pancreatic[7,8], and prostate[9] cancers. Cdk[5] modulates neuronal physiology through phosphorylating a variety of microtubule-associated and actin-binding proteins[10,11]. Cdk[5] may regulate cancer cell motility and invasion through remodeling of the cytoskeleton[12,13]. Phosphorylation of adducin in the MARCKS-related motif by protein kinase C (PKC) decreases its ability to bind spectrin and F-actin[25,26,27]. We demonstrate that Cdk5-mediated phosphorylation of ADD1 at T724 promotes epidermal growth factor (EGF)-induced cell migration and invasion
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