The activity status of cofilin is directly related to invasion, intravasation, and metastasis of mammary tumors.
Understanding the mechanisms controlling cancer cell invasion and metastasis constitutes a fundamental step in setting new strategies for diagnosis, prognosis, and therapy of metastatic cancers. LIM kinase1 (LIMK1) is a member of a novel class of serine-threonine protein kinases. Cofilin, a LIMK1 substrate, is essential for the regulation of actin polymerization and depolymerization during cell migration. Previous studies have made opposite conclusions as to the role of LIMK1 in tumor cell motility and metastasis, claiming either an increase or decrease in cell motility and metastasis as a result of LIMK1 over expression (Zebda, N., O. Bernard, M. Bailly, S. Welti, D.S. Lawrence, and J.S. Condeelis. 2000. J. Cell Biol. 151:1119-1128; Davila, M., A.R. Frost, W.E. Grizzle, and R. Chakrabarti. 2003. J. Biol. Chem. 278:36868-36875; Yoshioka, K., V. Foletta, O. Bernard, and K. Itoh. 2003. Proc. Natl. Acad. Sci. USA. 100:7247-7252; Nishita, M., C. Tomizawa, M. Yamamoto, Y. Horita, K. Ohashi, and K. Mizuno. 2005. J. Cell Biol. 171:349-359). We resolve this paradox by showing that the effects of LIMK1 expression on migration, intravasation, and metastasis of cancer cells can be most simply explained by its regulation of the output of the cofilin pathway. LIMK1-mediated decreases or increases in the activity of the cofilin pathway are shown to cause proportional decreases or increases in motility, intravasation, and metastasis of tumor cells.
Wang
Weigang
W
Department of Anatomy and Structural Biology and 2Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA. wgwang@aecom.yu.edu
Mouneimne
Ghassan
G
Sidani
Mazen
M
Wyckoff
Jeffrey
J
Chen
Xiaoming
X
Makris
Anastasia
A
Goswami
Sumanta
S
Bresnick
Anne R
AR
Condeelis
John S
JS
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D022081:Cell Surface Extensions / Q000235:genetics / Q000502:physiology; D002633:Chemotaxis / Q000235:genetics / Q000502:physiology; D051338:Cofilin 1 / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D054461:Lim Kinases; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D016019:Survival Analysis; D014162:Transfection
C495812:Cfl1 protein, rat; D051338:Cofilin 1; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D004815:Epidermal Growth Factor; D011494:Protein Kinases; D054461:Lim Kinases; C515894:Limk1 protein, rat