Interaction with LC8 is required for Pak1 nuclear import and is indispensable for zebrafish development.

Authors

Christine M Lightcap, Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PAFollow
Gabor Kari, Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PAFollow
Luis E Arias-Romero, Cancer Genetics and Signaling Program, Fox Chase Cancer Center, Philadelphia, PA
Jonathan Chernoff, Cancer Genetics and Signaling Program, Fox Chase Cancer Center, Philadelphia, PAFollow
Ulrich Rodeck, Department of Dermatology, Thomas Jefferson University, Philadelphia, PAFollow
John C Williams, Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA; Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CAFollow

Document Type

Article

Publication Date

6-1-2009

Comments

This article has been peer reviewed and is published in PLoS One 2009, 4(6). The published version is available at DOI: 10.1371/journal.pone.0006025. © Public Library of Science

Abstract

Pak1 (p21 activated kinase 1) is a serine/threonine kinase implicated in regulation of cell motility and survival and in malignant transformation of mammary epithelial cells. In addition, the dynein light chain, LC8, has been described to cooperate with Pak1 in malignant transformation of breast cancer cells. Pak1 itself may aid breast cancer development by phosphorylating nuclear proteins, including estrogen receptor alpha. Recently, we showed that the LC8 binding site on Pak1 is adjacent to the nuclear localization sequence (NLS) required for Pak1 nuclear import. Here, we demonstrate that the LC8-Pak1 interaction is necessary for epidermal growth factor (EGF)-induced nuclear import of Pak1 in MCF-7 cells, and that this event is contingent upon LC8-mediated Pak1 dimerization. In contrast, Pak2, which lacks an LC8 binding site but contains a nuclear localization sequence identical to that in Pak1, remains cytoplasmic upon EGF stimulation of MCF-7 cells. Furthermore, we show that severe developmental defects in zebrafish embryos caused by morpholino injections targeting Pak are partially rescued by co-injection of wild-type human Pak1, but not by co-injection of mutant Pak1 mRNA disrupting either the LC8 binding or the NLS site. Collectively, these results suggest that LC8 facilitates nuclear import of Pak1 and that this function is indispensable during vertebrate development.

Recommended Citation

Lightcap, Christine M; Kari, Gabor; Arias-Romero, Luis E; Chernoff, Jonathan; Rodeck, Ulrich; and Williams, John C, "Interaction with LC8 is required for Pak1 nuclear import and is indispensable for zebrafish development." (2009). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 31.
https://jdc.jefferson.edu/bmpfp/31

PubMed ID

19557173