Alphavbeta6-Fyn signaling promotes oral cancer progression.
We have previously shown that the integrin beta6 is neo-expressed in invasive oral squamous cell carcinoma (SCC) and is correlated with oral tumor progression. However, the mechanism by which the integrin beta6 promotes oral tumor progression is not well understood. The purpose of the present study was to determine whether integrin beta6 signaling activates Fyn and thus promotes oral squamous cell carcinoma progression. We analyzed the integrin beta6 signaling complex and investigated the function of these signaling molecules in oral SCC cells. We found that, upon ligation of the integrin beta6 with fibronectin, beta6 complexed with Fyn and activated it. The activation of Fyn recruited and activated focal adhesion kinase to this complex. This complex was necessary to activate Shc and to couple beta6 signaling to the Raf-ERK/MAPK pathway. This pathway transcriptionally activated the matrix metalloproteinase-3 gene and promoted oral SCC cell proliferation and experimental metastasis in vivo. These findings indicate that integrin beta6 signaling activates Fyn and thus promotes oral cancer progression.
Li
Xiaowu
X
Department of Stomatology, University of California-San Francisco, San Francisco, CA 94143-0512, USA.
Yang
Yongjian
Y
Hu
Yongmei
Y
Dang
Dongmin
D
Regezi
Joseph
J
Schmidt
Brian L
BL
Atakilit
Amha
A
Chen
Bing
B
Ellis
Duncan
D
Ramos
Daniel M
DM
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000473:pathology*; D002455:Cell Division; D045744:Cell Line, Tumor; D018450:Disease Progression; D004789:Enzyme Activation; D005353:Fibronectins; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051076:Proto-Oncogene Proteins c-fyn; D015398:Signal Transduction; D014062:Tongue Neoplasms / Q000209:etiology* / Q000473:pathology; D015533:Transcriptional Activation; D014162:Transfection
D000951:Antigens, Neoplasm; D005353:Fibronectins; D016023:Integrins; D011518:Proto-Oncogene Proteins; C073878:integrin alphavbeta6; D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C494960:Fyn protein, mouse; C496050:PTK2 protein, human; D051076:Proto-Oncogene Proteins c-fyn; C496051:Ptk2 protein, mouse; D019278:Matrix Metalloproteinase 3