Fibronectin maintains survival of mouse natural killer (NK) cells via CD11b/Src/beta-catenin pathway.
Tissue microenvironment and stroma-derived extracellular matrix (ECM) molecules play important roles in the survival and differentiation of cells. Mouse natural killer (NK) cells usually die within 24 hours once isolated ex vivo. Exogenous cytokines such as interleukin-12 (IL-12) and IL-15 are required to maintain the survival and activity of mouse NK cells cultured in vitro. Whether and how ECM molecules such as fibronectin can support the survival of NK cells remain unknown. We demonstrate that fibronectin, just like IL-15, can maintain survival of mouse NK cells in vitro. Furthermore, we show that fibronectin binds to the CD11b on NK cells, and then CD11b recruits and activates Src. Src can directly interact with beta-catenin and trigger nuclear translocation of beta-catenin. The activation of beta-catenin promotes extracellular signal-related kinase (ERK) phosphorylation, resulting in the increased expression of antiapoptotic protein B-cell leukemia 2 (Bcl-2), which may contribute to the maintenance of NK-cell survival. Consistently, fibronectin cannot maintain the survival of CD11b(-) NK cells and beta-catenin-deficient NK cells in vitro, and the number of NK cells is dramatically decreased in the beta-catenin-deficient mice. Therefore, fibronectin can maintain survival of mouse NK cells by activating ERK and up-regulating Bcl-2 expression via CD11b/Src/beta-catenin pathway.
Zhang
Ting
T
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, People's Republic of China.
Liu
Shuxun
S
Yang
Pengyuan
P
Han
Chaofeng
C
Wang
Jianli
J
Liu
Juan
J
Han
Yanmei
Y
Yu
Yizhi
Y
Cao
Xuetao
X
D000818:Animals; D001483:Base Sequence; D039481:CD11b Antigen / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005353:Fibronectins / Q000494:pharmacology*; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
D039481:CD11b Antigen; D017931:DNA Primers; D005353:Fibronectins; D019253:Proto-Oncogene Proteins c-bcl-2; D051176:beta Catenin; D019061:src-Family Kinases