title: A novel mechanism by which tissue transglutaminase activates signaling events that promote cell survival.
abstract: Tissue transglutaminase (tTG) functions as a GTPase and an acyl transferase that catalyzes the formation of protein cross-links. tTG expression is frequently up-regulated in human cancer, where it has been implicated in various aspects of cancer progression, including cell survival and chemo-resistance. However, the extent to which tTG cooperates with other proteins within the context of a cancer cell, versus its intrinsic ability to confer transformed characteristics to cells, is poorly understood. To address this question, we asked what effect the ectopic expression of tTG in a non-transformed cellular background would have on the behavior of the cells. Using NIH3T3 fibroblasts stably expressing a Myc-tagged form of tTG, we found that tTG strongly protected these cells from serum starvation-induced apoptosis and triggered the activation of the PI3-kinase/mTOR Complex 1 (mTORC1)/p70 S6-kinase pathway. We determined that tTG forms a complex with the non-receptor tyrosine kinase c-Src and PI3-kinase, and that treating cells with inhibitors to block tTG function (monodansylcadaverine; MDC) or c-Src kinase activity (PP2) disrupted the formation of this complex, and prevented tTG from activating the PI3-kinase pathway. Moreover, treatment of fibroblasts over-expressing tTG with PP2, or with inhibitors that inactivate components of the PI3-kinase pathway, including PI3-kinase (LY294002) and mTORC1 (rapamycin), ablated the tTG-promoted survival of the cells. These findings demonstrate that tTG has an intrinsic capability to stimulate cell survival through a novel mechanism that activates PI3-kinase signaling events, thus highlighting tTG as a potential target for the treatment of human cancer.
authors.affiliation: From the Department of Molecular Medicine, Cornell University, Ithaca, New York 14853.
authors.forename: Lindsey K
authors.initials: LK
authors.lastname: Boroughs
authors.forename: Marc A
authors.initials: MA
authors.lastname: Antonyak
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cerione
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002103:Cadaverine / Q000031:analogs & derivatives / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011743:Pyrimidines / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D002103:Cadaverine; D002867:Chromones; D004791:Enzyme Inhibitors; D019204:GTP-Binding Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D009025:Morpholines; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011743:Pyrimidines; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D011503:Transglutaminases; D019061:src-Family Kinases; C412373:AG 1879; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C000631346:CSK protein, human; C008542:monodansylcadaverine
keywords: Akt; Apoptosis; Cell Survival; PI3-kinase (PI3K); Src; Tissue Transglutaminase; Transformation; p70 S6-kinase