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LIM Kinase 1 Is Essential for the Invasive Growth of Prostate Epithelial Cells - Implications in Prostate Cancer

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LIM Kinase 1 Is Essential for the Invasive Growth of Prostate Epithelial Cells - Implications in Prostate Cancer University of Central Florida STARS Faculty Bibliography 2000s Faculty Bibliography 1-1-2003 LIM kinase 1 is essential for the invasive growth of prostate epithelial cells - Implications in prostate cancer Monica Davila University of Central Florida Andra R. Frost William E. Grizzle Ratna Chakrabarti University of Central Florida Find similar works at: https://stars.library.ucf.edu/facultybib2000 University of Central Florida Libraries http://library.ucf.edu This Article is brought to you for free and open access by the Faculty Bibliography at STARS. It has been accepted for inclusion in Faculty Bibliography 2000s by an authorized administrator of STARS. For more information, please contact [email protected]. Recommended Citation Davila, Monica; Frost, Andra R.; Grizzle, William E.; and Chakrabarti, Ratna, "LIM kinase 1 is essential for the invasive growth of prostate epithelial cells - Implications in prostate cancer" (2003). Faculty Bibliography 2000s. 2561. https://stars.library.ucf.edu/facultybib2000/2561 THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 278, No. 38, Issue of September 19, pp. 36868–36875, 2003 © 2003 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A. LIM Kinase 1 Is Essential for the Invasive Growth of Prostate Epithelial Cells IMPLICATIONS IN PROSTATE CANCER* Received for publication, June 12, 2003 Published, JBC Papers in Press, June 23, 2003, DOI 10.1074/jbc.M306196200 Monica Davila‡, Andra R. Frost§, William E. Grizzle§, and Ratna Chakrabarti‡¶ From the ‡Department of Molecular Biology and Microbiology University of Central Florida, Orlando, Florida 32826 and §Department of Pathology, University of Alabama, Birmingham, Alabama 35294 Mammalian LIM kinase 1 (LIMK1) is involved in reor- activity of LIMK1 is regulated by distinct members of the Rho ganization of actin cytoskeleton through inactivating subfamily of small GTPases (Rho, Rac, and Cdc42), which phosphorylation of the ADF family protein cofilin, controls actin filament dynamics and focal adhesions assembly Downloaded from which depolymerizes actin filaments. Maintenance of in response to extra- and intracellular stimuli. Rho, Rac, and the actin dynamics in an ordered fashion is essential for Cdc42 induce formation of stress fibers, assembly of lamellipo- stabilization of cell shape or promotion of cell motility dia and membrane ruffles, and regulation of filopodial protru- depending on the cell type. These are the two key phe- sions, respectively (6). LIMK1 has been shown to mediate spe- nomena that may become altered during acquisition of cifically Rac-induced actin cytoskeleton reorganization and the metastatic phenotype by cancer cells. Here we show focal adhesion complexes (5, 7, 8). Rac-induced activation of http://www.jbc.org/ that LIMK1 is overexpressed in prostate tumors and in LIMK1 is mediated by PAK1, which phosphorylates LIMK1 on prostate cancer cell lines, that the concentration of its Thr508 residue (9). Other studies also proposed that Rho- phosphorylated cofilin is higher in metastatic prostate cancer cells, and that a partial reduction of LIMK1 al- and Cdc42- induced cytoskeletal changes are mediated through phosphorylation of LIMK1 by Rho-dependent protein kinase tered cell proliferation by arresting cells at G2/M, changed cell shape, and abolished the invasiveness of ROCK (10) and Cdc42-regulated protein kinase PAK4 (11) and metastatic prostate cancer cells. We also show that the MRCK␣ (12). at UCF Health Sciences Library on September 24, 2019 ectopic expression of LIMK1 promotes acquisition of The non-catalytic domain of LIMK1 contains two tandem invasive phenotype by the benign prostate epithelial repeats of a LIM motif, a putative zinc binding motif, and a cells. Our data provide evidence of a novel role of LIMK1 PDZ domain, which contains two tandem nuclear exit signal in regulating cell division and invasive property of pros- sequences (7). LIMK1 also contains a nuclear localization sig- tate cancer cells and indicate that the effect is not me- nal-like basic cluster sequence. The non-catalytic domain of diated by phosphorylation of cofilin. Our study corre- LIMK1 has been shown to have effects on cytoskeleton reorga- lates with the recent observations showing a metastasis- nization independent of its kinase activity. Specific regions of associated chromosomal gain on 7q11.2 in prostate the non-catalytic domain (LIM or PDZ) inhibit neurite out- cancer, suggesting a possible gain in LIMK1 DNA growth in differentiating PC12 cells in response to Ras, neuro- (7q11.23). nal growth factor (NGF) or a ROCK inhibitor without altering endogenous LIMK1 activity (13, 14). These observations sug- gest that the non-catalytic domain of LIMK1 is involved in 1 LIM kinase 1 (LIMK1) belongs to a novel dual specificity regulating cellular processes though protein-protein interac- (serine/threonine and tyrosine) kinase family that contain two tion. LIMK1 also physically interacts through its LIM domain amino-terminal LIM domains (1). LIMK1 gene is expressed with the cytoplasmic tail of neuregulins, a family of transmem- predominantly in brain and in developing neural tissues (2), brane proteins that functions as receptor tyrosine kinase li- and its deletion (microdeletion of chromosome 7q11.23) is typ- gands. These proteins are known to be involved in the regula- ical for Williams syndrome (3). Cofilin, one of the actin-binding tion of synapse formation and maintenance, cell proliferation, proteins, considered to be a potent regulator of the actin dy- apoptosis, differentiation, and neuronal migration (15). Dele- namics (4) by means of its activity in F-actin depolymerization, tion experiments have shown that the lack of LIM and PDZ is the only known substrate of LIMK1. The function of cofilin is domains enhances the effect of LIMK1 on actin cytoskeleton inhibited by phosphorylation at the Ser-3 residue (5) by (16). In addition, expression of a kinase-inactive form of the LIMK1, which leads to accumulation of F-actin. The catalytic protein blocked the effect of the native LIMK1 (5). These find- ings suggest an inhibitory role of the non-catalytic domain in * The costs of publication of this article were defrayed in part by the the regulation of the kinase activity of LIMK1. payment of page charges. This article must therefore be hereby marked Reorganization of cytoskeleton is an essential feature of mo- “advertisement” in accordance with 18 U.S.C. Section 1734 solely to tility, detachment, and invasion of cancer cells. Individual indicate this fact. members of the Rho family, such as Rac and Cdc42, induce ¶ Supported by NCI, National Institutes of Health Grant CA81329 distinct actin remodeling events, work together at the leading and by an award from the Florida Hospital Gala Endowment for On- cologic Research. To whom correspondence should be addressed: Dept. edge of the cell, and coordinate lamellipodial and filopodial of Molecular Biology and Microbiology, University of Central Florida, extensions, whereas Rho activates accumulation of stress fibers 12722 Research Pkwy., Orlando, FL 32826. Tel.: 407-882-2258; Fax: through activation of ROCK (17). Formation and stabilization 407-384-2062; E-mail: [email protected]. of actin filaments are the key events downstream of Rac and 1 The abbreviations used are: LIMK1, LIM kinase 1; NGF, nerve growth factor; EGF, epidermal growth factor; BPH-1, benign prostatic Cdc42, which provide the protrusive force for cellular exten- hyperplasia cells. sions at the leading edge of the migratory cells (18). Seemingly, 36868 This paper is available on line at http://www.jbc.org LIM Kinase 1 and Prostate Cancer 36869 these events are critical for the invasive behavior of the cancer cells, as the inhibition of Rho kinase activity has been shown to reduce invasive progress of prostate cancer cells in vivo (19). Rho proteins are activated by growth factor receptors and their ligands, for example, EGF and NGF and their respective re- ceptors erbB2 and Trk. Cellular-erbB2 and Trk are often over- expressed and activated in various types of cancers including prostate cancer (20–22). Furthermore, c-erbB2 was shown to enhance the invasiveness and metastatic potential of cancer cells (20). Similarly, NGF and Trk expressions in prostate cancer cells coincide with transformation to a malignant phe- notype capable of invading along the perineural space and extracapsular metastasis to a distant site (23). As evident from membrane ruffling and lamellipodia formation, EGF- and NGF-induced increased invasion of prostate tumor cells is me- diated through Rac (24). Therefore, it is likely that Rac-medi- ated activation of actin reorganization is mediated through LIMK1. cDNA microarry and differential display reverse-tran- Downloaded from scription PCR analyses revealed an up-regulation of LIMK1 mRNA (25) and LIMK1 as the elastin-linked gene (26) in pros- tate adenocarcinoma cells. This study reports that LIMK1 is overexpressed in prostate adnocarcinomatous tissues and in malignant prostate cell lines and is essential for the invasive property and growth of prostate cancer cells, and the effect is http://www.jbc.org/ FIG.1. LIMK1 is differentially expressed in human prostate not mediated through inactivating phosphorylation of cofilin. cell lines and prostate tissues. a, immunoblot analysis of LIMK1 in EXPERIMENTAL PROCEDURES total lysates of human prostate cell lines. b, expression of LIMK1 in prostate tissues. Upper panel, Normal/benign areas. Lower panel, can- Cell Culture, Transfection, and Isolation of Stable Cell Line—PC3, cerous glands. Upper and lower left, Hematoxylin/eosin-stained slides. DU145, LNCaP (ATCC), PrEC (Clonetics), BPH-1 (a gift from P. Magnification, ϫ100. Upper and lower right, areas from normal and Narayan, Celebration, FL), p69, M21, and M12 (gift from J. Ware, cancerous tissues are shown in higher magnification (ϫ200). Arrows Richmond, VA) were maintained in RPMI (DU145, LNCaP, p69, M21, indicate light staining in basal cells in normal/benign areas (upper at UCF Health Sciences Library on September 24, 2019 and M12), Ham-12 (PC3), DMEM (BPH-1) and in specified medium panel) and intense staining in cells in cancerous areas (lower panel).
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