title: α-Actinin-4 enhances colorectal cancer cell invasion by suppressing focal adhesion maturation.
abstract: α-Actinins (ACTNs) are known to crosslink actin filaments at focal adhesions in migrating cells. Among the four isoforms of mammalian ACTNs, ACTN1 and ACTN4 are ubiquitously expressed. Recently, ACTN4 was reported to enhance cancer cell motility, invasion, and metastasis. However, the mechanism by which ACTN4 drives these malignant phenotypes remains unclear. Here, we show that ACTN4, but not ACTN1, induces the formation of immature focal adhesions in DLD-1 cells, leading to the rapid turnover of focal adhesions. Interestingly, zyxin (ZYX) assembly to focal adhesions was markedly decreased in ACTN4-expressing DLD-1 cells, while the recruitment of paxillin (PAX) occurred normally. On the other hand, in ACTN1-expressing DLD-1 cells, PAX and ZYX were normally recruited to focal adhesions, suggesting that ACTN4 specifically impairs focal adhesion maturation by inhibiting the recruitment of ZYX to focal complexes. Using purified recombinant proteins, we found that ZYX binding to ACTN4 was defective under conditions where ZYX binding to ACTN1 was observed. Furthermore, Matrigel invasion of SW480 cells that express high endogenous levels of ACTN4 protein was inhibited by ectopic expression of ACTN1. Altogether, our results suggest that ZYX defective binding to ACTN4, which occupies focal adhesions instead of ACTN1, induces the formation of immature focal adhesions, resulting in the enhancement of cell motility and invasion.
authors: Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
authors: Miki
authors: M
authors: Fukumoto
authors: Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe, Hyogo 657-8501, Japan.
authors: Shusaku
authors: S
authors: Kurisu
authors: Pathology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors: Tesshi
authors: T
authors: Yamada
authors: Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
authors: Tadaomi
authors: T
authors: Takenawa
mesh_terms: D000185:Actinin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D022001:Focal Adhesions / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D051419:Paxillin / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D060589:Zyxin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C526905:ACTN1 protein, human; C111453:ACTN4 protein, human; D051419:Paxillin; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C092842:ZYX protein, human; D060589:Zyxin; D000185:Actinin