EGF potentiated oncogenesis requires a tissue transglutaminase-dependent signaling pathway leading to Src activation.
EGF receptor (EGFR) signaling in human cancers elicits changes in protein-expression patterns that are crucial for potentiating tumor growth. Identifying those proteins with expression regulated by the EGFR and determining how they contribute to malignancy is fundamental for the development of more effective strategies to treat cancer. Here, we show that tissue transglutaminase (tTG) is one such protein. EGF up-regulates tTG expression in human breast-cancer cells, and knock-downs of tTG or the treatment of breast cancer cells with a tTG inhibitor blocks their EGF-stimulated anchorage-independent growth. We further show that the combined actions of Ras and Cdc42, leading to the activation of PI 3-kinase and NFkappaB, provide a mechanism by which EGF can up-regulate tTG in breast-cancer cells. Moreover, overexpression of wild-type tTG, but not its transamidation-defective counterpart, fully mimics the growth advantages afforded by EGF to these cancer cells. Surprisingly, the tTG-promoted growth of breast-cancer cells is dependent on its ability to activate the Src tyrosine kinase as an outcome of a complex formed between tTG and the breast-cancer marker and intermediate filament protein keratin-19. These findings identify tTG as a key participant in an EGFR/Src-signaling pathway in breast-cancer cells and a potential target for inhibiting EGFR-promoted tumor progression.
Li
Bo
B
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
Antonyak
Marc A
MA
Druso
Joseph E
JE
Cheng
Le
L
Nikitin
Alexander Yu
AY
Cerione
Richard A
RA
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D019204:GTP-Binding Proteins; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D053539:Keratin-19 / Q000235:genetics / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D011485:Protein Binding; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D015398:Signal Transduction; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D053539:Keratin-19; D004815:Epidermal Growth Factor; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019061:src-Family Kinases; D019204:GTP-Binding Proteins; D015689:Oncogene Protein p21(ras); D020764:cdc42 GTP-Binding Protein