Journal of Biological Chemistry
Cell Transformation, Neoplastic--genetics; Epithelial Cells--metabolism; Gene Expression Regulation, Neoplastic; Intracellular Signaling Peptides and Proteins--genetics; Prostate--metabolism; p21-Activated Kinases--genetics
Upon growth factor stimulation, PAK1 is recruited to the plasma membrane and activated by a mechanism that requires its phosphorylation at S223 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, we observe that 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-CK2α-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.
Yong-Bae Kim, Yong Jae Shin, Adhiraj Roy, and Jeong-Ho Kim. (2015). The Role of the Pleckstrin Homology Domain-containing Protein CKIP-1 in Activation of p21-activated Kinase 1 (PAK1). Journal of Biological Chemistry,