This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, S. Articles by Marcus, A. I. Search for Related Content PubMed PubMed Citation Articles by Zhang, S. Articles by Marcus, A. I.

The Tumor Suppressor LKB1 Regulates Lung Cancer Cell Polarity by Mediating cdc42 Recruitment and Activity

Departments of ¹ Hematology and Oncology and ² Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia

Requests for reprints: Adam I. Marcus, Winship Cancer Institute, Emory University, Room D4054, 1365C Clifton Road, Atlanta, GA 30043. Phone: 404-778-4597; E-mail: adam.marcus{at}emoryhealthcare.org.

Key Words: LKB1 • cdc42 • polarity • actin • PAK

The tumor suppressor LKB1 is mutated in 30% of non–small cell lung cancer (NSCLC) tumors and cell lines and is proposed to be a key regulator of epithelial cell polarity; however, how LKB1 regulates cancer cell polarity is not known. The experiments described herein show for the first time that LKB1 is a dynamic, actin-associated protein that rapidly polarizes to the leading edge of motile cancer cells. LKB1 proves to be essential for NSCLC polarity, because LKB1 depletion results in classic cell polarity defects, such as aberrant Golgi positioning, reduced lamellipodia formation, and aberrant morphology. To probe how LKB1 regulates these events, we show that LKB1 colocalizes at the cellular leading edge with two key components of the polarity pathway — the small rho GTPase cdc42 and its downstream binding partner p21-activated kinase (PAK). Importantly, LKB1 functionality is required for cdc42 polarization to the leading edge, maintaining active cdc42 levels, and downstream PAK phosphorylation. To do this, LKB1 interacts only with active form of cdc42 and PAK, but not with inactive cdc42. Taken together, these results show that LKB1 is a critical mediator of the NSCLC polarity program in lung cancer cells through a novel LKB1-cdc42-PAK pathway. [Cancer Res 2008;68(3):740–8]

This article has been cited by other articles:

				M. Jansen, J. P. ten Klooster, G. J. Offerhaus, and H. Clevers LKB1 and AMPK Family Signaling: The Intimate Link Between Cell Polarity and Energy Metabolism Physiol Rev, July 1, 2009; 89(3): 777 - 798. [Abstract] [Full Text] [PDF]

				W. J. Nelson Remodeling Epithelial Cell Organization: Transitions Between Front-Rear and Apical-Basal Polarity Cold Spring Harb Perspect Biol, July 1, 2009; 1(1): a000513 - a000513. [Abstract] [Full Text] [PDF]

				F. Causeret, M. Terao, T. Jacobs, Y. V. Nishimura, Y. Yanagawa, K. Obata, M. Hoshino, and M. Nikolic The p21-Activated Kinase Is Required for Neuronal Migration in the Cerebral Cortex Cereb Cortex, April 1, 2009; 19(4): 861 - 875. [Abstract] [Full Text] [PDF]

				S. Rodriguez-Nieto and M. Sanchez-Cespedes BRG1 and LKB1: tales of two tumor suppressor genes on chromosome 19p and lung cancer Carcinogenesis, April 1, 2009; 30(4): 547 - 554. [Abstract] [Full Text] [PDF]

				D. Fan, C. Ma, and H. Zhang The molecular mechanisms that underlie the tumor suppressor function of LKB1 Acta Biochim Biophys Sin, February 1, 2009; 41(2): 97 - 107. [Abstract] [Full Text] [PDF]

				R. S. Herbst, J. V. Heymach, and S. M. Lippman Lung Cancer N. Engl. J. Med., September 25, 2008; 359(13): 1367 - 1380. [Full Text] [PDF]