EGF potentiated oncogenesis requires a tissue transglutaminase-dependent signaling pathway leading to Src activation

Abstract

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 breastcancer 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 NFκB, 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.breast cancer | keratin 19

Epidermal Growth Factor Receptor-mediated Tissue Transglutaminase Overexpression Couples Acquired Tumor Necrosis Factor-related Apoptosis-inducing Ligand Resistance and Migration through c-FLIP and MMP-9 Proteins in Lung Cancer Cells

“…Although increased TGM2 expression in cancer cells has been linked to increased drug resistance, metastasis, and poor patient survival (36,37,40), to our knowledge, this is the first report showing that TGM2 is overexpressed when acquired TRAIL resistance arises with the association of increased cell migration and invasion. Although the regulation of TGM2 expression is complex, EGFR-mediated cell signaling is implicated in up-regulation of TGM2 expression in cancer cells (32). In this study, we reveal that EGFR-mediated activation of JNK and ERK increases TGM2 expression, which contributes to acquired TRAIL resistance and cell migration.…”

“…Because EGFR signaling was reported to up-regulate TGM2 expression (32,33), we examined the expression and activity of EGFR in the TR cells. Indeed, the active form (phosphorylated) of EGFR was markedly elevated, whereas the total EGFR protein was slightly increased, in A549-TR and H1568-TR cells (Fig.…”

Overexpression of Transglutaminase in theDrosophilaWing Imaginal Disc Induced an Extra Wing Crossvein Phenotype

“…During the normal development of Drosophila, dTG-A may be involved in the regulatory process of wing crossvein formation through control of Egfr signaling. EGF upregulates tissue-type TG in animal cells such as rat primary cultured hepatocytes 14) and human cancer cells, 15) but upregulation of the Egfrsignaling pathway by TG has not been reported to our knowledge.…”

A Conserved Rod Domain Phosphotyrosine That Is Targeted by the Phosphatase PTP1B Promotes Keratin 8 Protein Insolubility and Filament Organization*

“…For example, in cells expressing constitutively active Src kinase, K19 becomes phosphorylated at Tyr-391, which then preferentially partitions into the soluble compartment (22). Furthermore, the interaction between Src and K19 appears to act as a critical facilitator of EGF-stimulated oncogenesis because it is necessary for the activation of Src by EGF-stimulated tissue transglutaminase (40). On the other hand, a phosphorylation-independent association between Src and K6, which is induced in keratinocytes during wound repair, inhibits Src kinase activity, resulting in attenuated keratinocyte migration (41).…”