Abstract
Upon growth factor stimulation, PAK1 is recruited to the plasma membrane and activated by a mechanism that requires its phosphorylation at Ser-223 by the protein kinase CK2. However, the upstream signaling molecules that regulate this phosphorylation event are not clearly defined. Here, we demonstrate a major role of the CK2α-interacting protein CKIP-1 in activation of PAK1. CK2α, CKIP-1, and PAK1 are translocated to membrane ruffles in response to the epidermal growth factor (EGF), where CKIP-1 mediates the interaction between CK2α and PAK1 in a PI3K-dependent manner. Consistently, PAK1 mediates phosphorylation and modulation of the activity of p41-Arc, one of its plasma membrane substrate, in a fashion that requires PI3K and CKIP-1. Moreover, CKIP-1 knockdown or PI3K inhibition suppresses PAK1-mediated cell migration and invasion, demonstrating the physiological significance of the PI3K-CKIP-1-CK2-PAK1 signaling pathway. Taken together, these findings identify a novel mechanism for the activation of PAK1 at the plasma membrane, which is critical for cell migration and invasion.
Highlights
p21-activated kinase 1 (PAK1) is phosphorylated and activated by the protein kinase CK2 in response to epidermal growth factor (EGF)
PAK1 is recruited to the plasma membrane and activated by a mechanism that requires its phosphorylation at Ser-223 by the protein kinase CK2
We establish the role of CKIP-1 in the PI3K activation of PAK1 in response to EGF
Summary
PAK1 is phosphorylated and activated by the protein kinase CK2 in response to EGF. Results: Upon EGF stimulation, CKIP-1 recruits CK2 to PAK1 in membrane ruffles in a PI3K-dependent manner. CKIP-1 knockdown or PI3K inhibition suppresses PAK1-mediated cell migration and invasion, demonstrating the physiological significance of the PI3K-CKIP-1-CK2-PAK1 signaling pathway Taken together, these findings identify a novel mechanism for the activation of PAK1 at the plasma membrane, which is critical for cell migration and invasion. CKIP-1 appears to associate with the plasma membrane through binding to phosphoinositides and to regulate muscle differentiation in mouse myoblast C2C12 cells [24] as well as myoblast fusion in mouse and zebrafish, in PI3K-dependent fashion [25] These observations have raised the possibility that CKIP-1 may serve as a key controller of cellular processes regulated by PI3K. Inhibition of either CKIP-1 or PI3K activity blocks PAK1-mediated actin cytoskeleton dynamics and cell migration These results demonstrate the role of CKIP-1 in EGF-induced. Activation of PAK1, providing a novel regulatory mechanism for PAK1 signaling
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