title: The Role of the Pleckstrin Homology Domain-containing Protein CKIP-1 in Activation of p21-activated Kinase 1 (PAK1).
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.
authors.affiliation: Department of Biochemistry and Molecular Medicine, The George Washington University Medical Center, Washington, DC 20037 and.
authors.forename: Yong-Bae
authors.initials: YB
authors.lastname: Kim
authors.affiliation: Samsung Biomedical Research Institute and Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
authors.forename: Yong Jae
authors.initials: YJ
authors.lastname: Shin
authors.affiliation: Department of Biochemistry and Molecular Medicine, The George Washington University Medical Center, Washington, DC 20037 and.
authors.forename: Adhiraj
authors.initials: A
authors.lastname: Roy
authors.affiliation: Department of Biochemistry and Molecular Medicine, The George Washington University Medical Center, Washington, DC 20037 and. Electronic address: jh_kim@gwu.edu.
authors.forename: Jeong-Ho
authors.initials: JH
authors.lastname: Kim
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics / Q000378:metabolism; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011467:Prostate / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054462:p21-Activated Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D047390:Casein Kinase II; D004815:Epidermal Growth Factor; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D054462:p21-Activated Kinases; C460821:ARPC1B protein, human; C408877:PLEKHO1 protein, human; C515903:PAK1 protein, human
keywords: prostate cancer; protein kinase; protein phosphorylation; signal transduction; signaling