Transglutaminase 2 (TG2, tissue transglutaminase) is a multifunctional protein involved in cross-linking a variety of proteins, including retinoblastoma protein (Rb). Here we show that Rb is also a substrate for the recently identified serine/threonine kinase activity of TG2 and that TG2 phosphorylates Rb at the critically important Ser(780) residue. Furthermore, phosphorylation of Rb by TG2 destabilizes the Rb center dot E2F1 complex. TG2 phosphorylation of Rb was abrogated by high Ca2+ concentrations, whereas TG2 transamidating activity was inhibited by ATP. TG2 was itself phosphorylated by protein kinase A (PKA). Phosphorylation of TG2 by PKA attenuated its transamidating activity and enhanced its kinase activity. Activation of PKA in mouse embryonic fibroblasts (MEF) with dibutyryl-cAMP enhanced phosphorylation of both TG2 and Rb by a process that was inhibited by the PKA inhibitor H89. Treatment with dibutyryl-cAMP enhanced Rb phosphorylation in MEFtg2+/+ cells but not in MEFtg2-/- cells. These data indicate that Rb is a substrate for TG2 kinase activity and suggest that phosphorylation of Rb, which results from activation of PKA in fibroblasts, is indirect and requires TG2 kinase activity.

Mishra, S., Melino, G., Murphy, L.j. (2007). Transglutaminase 2 kinase activity facilitates protein kinase A-induced phosphorylation of retinoblastoma protein. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 282(25), 18108-18115 [10.1074/jbc.M607413200].

Transglutaminase 2 kinase activity facilitates protein kinase A-induced phosphorylation of retinoblastoma protein

MELINO, GENNARO;
2007-01-01

Abstract

Transglutaminase 2 (TG2, tissue transglutaminase) is a multifunctional protein involved in cross-linking a variety of proteins, including retinoblastoma protein (Rb). Here we show that Rb is also a substrate for the recently identified serine/threonine kinase activity of TG2 and that TG2 phosphorylates Rb at the critically important Ser(780) residue. Furthermore, phosphorylation of Rb by TG2 destabilizes the Rb center dot E2F1 complex. TG2 phosphorylation of Rb was abrogated by high Ca2+ concentrations, whereas TG2 transamidating activity was inhibited by ATP. TG2 was itself phosphorylated by protein kinase A (PKA). Phosphorylation of TG2 by PKA attenuated its transamidating activity and enhanced its kinase activity. Activation of PKA in mouse embryonic fibroblasts (MEF) with dibutyryl-cAMP enhanced phosphorylation of both TG2 and Rb by a process that was inhibited by the PKA inhibitor H89. Treatment with dibutyryl-cAMP enhanced Rb phosphorylation in MEFtg2+/+ cells but not in MEFtg2-/- cells. These data indicate that Rb is a substrate for TG2 kinase activity and suggest that phosphorylation of Rb, which results from activation of PKA in fibroblasts, is indirect and requires TG2 kinase activity.
2007
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/11 - BIOLOGIA MOLECOLARE
English
Con Impact Factor ISI
Amino acids; Crosslinking; Enzyme activity; Fibroblasts; Phosphorylation; Proteins; Kinase activity; Transamidating activity; Transglutaminase; Enzyme kinetics; bucladesine; cyclic AMP dependent protein kinase; enzyme; n [2 (4 bromocinnamylamino)ethyl] 5 isoquinolinesulfonamide; retinoblastoma protein; serine; threonine; transglutaminase 2 kinase; animal cell; article; controlled study; enzyme activity; fibroblast; human; human cell; mouse; nonhuman; priority journal; protein phosphorylation; Adenosine Triphosphate; Animals; Apoptosis; Calcium; Cell Cycle; Cell Line; Cyclic AMP-Dependent Protein Kinases; Fibroblasts; GTP-Binding Proteins; Humans; Mice; Phosphorylation; Retinoblastoma Protein; S Phase; Serine; Transglutaminases
Mishra, S., Melino, G., Murphy, L.j. (2007). Transglutaminase 2 kinase activity facilitates protein kinase A-induced phosphorylation of retinoblastoma protein. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 282(25), 18108-18115 [10.1074/jbc.M607413200].
Mishra, S; Melino, G; Murphy, Lj
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/26668
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