Tetraspan TM4SF5-dependent direct activation of FAK and metastatic potential of hepatocarcinoma cells.
Transmembrane 4 L six family member 5 (TM4SF5) plays an important role in cell migration, and focal adhesion kinase (FAK) activity is essential for homeostatic and pathological migration of adherent cells. However, it is unclear how TM4SF5 signaling mediates the activation of cellular migration machinery, and how FAK is activated during cell adhesion. Here, we showed that direct and adhesion-dependent binding of TM4SF5 to FAK causes a structural alteration that may release the inhibitory intramolecular interaction in FAK. In turn, this may activate FAK at the cell's leading edge, to promote migration/invasion and in vivo metastasis. TM4SF5-mediated FAK activation occurred during integrin-mediated cell adhesion. TM4SF5 was localized at the leading edge of the cells, together with FAK and actin-organizing molecules, indicating a signaling link between TM4SF5/FAK and actin reorganization machinery. Impaired interactions between TM4SF5 and FAK resulted in an attenuated FAK phosphorylation (the signaling link to actin organization machinery) and the metastatic potential. Our findings demonstrate that TM4SF5 directly binds to and activates FAK in an adhesion-dependent manner, to regulate cell migration and invasion, suggesting that TM4SF5 is a promising target in the treatment of metastatic cancer.
Interdisciplinary Program in Genetic Engineering, Research Institute of Pharmaceutical Sciences, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea (Republic of).
Oisun
O
Jung
Suyong
S
Choi
Sun-Bok
SB
Jang
Sin-Ae
SA
Lee
Ssang-Taek
ST
Lim
Yoon-Ju
YJ
Choi
Hye-Jin
HJ
Kim
Do-Hee
DH
Kim
Tae Kyoung
TK
Kwak
Hyeonjung
H
Kim
Minkyung
M
Kang
Mi-Sook
MS
Lee
Sook Young
SY
Park
Jihye
J
Ryu
Doyoung
D
Jeong
Hae-Kap
HK
Cheong
Hyun Jeong
HJ
Kim
Ki Hun
KH
Park
Bong-Jin
BJ
Lee
David D
DD
Schlaepfer
Jung Weon
JW
Lee
D000595:Amino Acid Sequence; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D004789:Enzyme Activation; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D015398:Signal Transduction; D059470:Tetraspanins / Q000235:genetics* / Q000378:metabolism
C485950:TSPAN32 protein, human; D059470:Tetraspanins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human