TY - JOUR
T1 - The TWEAK receptor Fn14 is an Src-inducible protein and a positive regulator of Src-driven cell invasion
AU - Cheng, Emily
AU - Whitsett, Timothy G.
AU - Tran, Nhan L.
AU - Winkles, Jeffrey A.
N1 - Publisher Copyright:
© 2014 American Association for Cancer Research.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - The TNF receptor superfamily member Fn14 (TNFRSF12A) is the sole signaling receptor for the proinflammatory cytokine TWEAK (TNFSF12). TWEAK:Fn14 engagement stimulates multiple signal transduction pathways, including the NF-kB pathway, and this triggers important cellular processes (e.g., growth, differentiation, migration, and invasion). The TWEAK-Fn14 axis is thought to be a major physiologic mediator of tissue repair after acute injury. Various studies have revealed that Fn14 is highly expressed in many solid tumor types, and that Fn14 signaling may play a role in tumor growth and metastasis. Previously, it was shown that Fn14 levels are frequently elevated in non-small cell lung cancer (NSCLC) tumors and cell lines that exhibit constitutive EGFR phosphorylation (activation). Furthermore, elevated Fn14 levels increased NSCLC cell invasion in vitro and lung metastatic tumor colonization in vivo. The present study reveals that EGFR-mutant NSCLC cells that express high levels of Fn14 exhibit constitutive activation of the cytoplasmic tyrosine kinase Src, and that treatment with the Src family kinase (SFK) inhibitor dasatinib decreases Fn14 gene expression at both the mRNA and protein levels. Importantly, siRNA-mediated depletion of the SFK member Src in NSCLC cells also decreases Fn14 expression. Finally, expression of the constitutively active v-Src oncoprotein in NIH 3T3 cells induces Fn14 gene expression, and NIH 3T3/v-Src cells require Fn14 expression for full invasive capacity.
AB - The TNF receptor superfamily member Fn14 (TNFRSF12A) is the sole signaling receptor for the proinflammatory cytokine TWEAK (TNFSF12). TWEAK:Fn14 engagement stimulates multiple signal transduction pathways, including the NF-kB pathway, and this triggers important cellular processes (e.g., growth, differentiation, migration, and invasion). The TWEAK-Fn14 axis is thought to be a major physiologic mediator of tissue repair after acute injury. Various studies have revealed that Fn14 is highly expressed in many solid tumor types, and that Fn14 signaling may play a role in tumor growth and metastasis. Previously, it was shown that Fn14 levels are frequently elevated in non-small cell lung cancer (NSCLC) tumors and cell lines that exhibit constitutive EGFR phosphorylation (activation). Furthermore, elevated Fn14 levels increased NSCLC cell invasion in vitro and lung metastatic tumor colonization in vivo. The present study reveals that EGFR-mutant NSCLC cells that express high levels of Fn14 exhibit constitutive activation of the cytoplasmic tyrosine kinase Src, and that treatment with the Src family kinase (SFK) inhibitor dasatinib decreases Fn14 gene expression at both the mRNA and protein levels. Importantly, siRNA-mediated depletion of the SFK member Src in NSCLC cells also decreases Fn14 expression. Finally, expression of the constitutively active v-Src oncoprotein in NIH 3T3 cells induces Fn14 gene expression, and NIH 3T3/v-Src cells require Fn14 expression for full invasive capacity.
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U2 - 10.1158/1541-7786.MCR-14-0411
DO - 10.1158/1541-7786.MCR-14-0411
M3 - Article
C2 - 25392346
AN - SCOPUS:84928012537
SN - 1541-7786
VL - 13
SP - 575
EP - 583
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 3
ER -