c-Abl mediates high NaCl-induced phosphorylation and activation of the transcription factor TonEBP/OREBP

• Published in: The FASEB journal 2010-11, Vol.24 (11), p.4325-4335
• Main Authors: Gallazzini, Morgan, Yu, Ming-Jiun, Gunaratne, Ruwan, Burg, Maurice B, Ferraris, Joan D
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Benzamides; Cell Line; Enzyme Activation - drug effects; HEK293 Cells; HeLa Cells; Humans; hypertonicity; Imatinib Mesylate; Kidney Medulla - metabolism; kinase; Male; Molecular Sequence Data; NFAT5; NFATC Transcription Factors - metabolism; Phosphorylation - drug effects; Piperazines - pharmacology; Protein Transport - physiology; Proto-Oncogene Proteins c-abl - antagonists & inhibitors; Proto-Oncogene Proteins c-abl - genetics; Proto-Oncogene Proteins c-abl - metabolism; Pyrimidines - pharmacology; Rats; Rats, Sprague-Dawley; Research Communications; Sequence Alignment; signaling; Sodium Chloride - pharmacology; Transcriptional Activation - physiology; Tyrosine - metabolism
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.10-157362

The transcription factor TonEBP/OREBP promotes cell survival during osmotic stress. High NaCl-induced phosphorylation of TonEBP/OREBP at tyrosine-143 was known to be an important factor in increasing its activity in cell culture. We now find that TonEBP/OREBP also is phosphorylated at tyrosine-143 in rat renal inner medulla, dependent on the interstitial osmolality. c-Abl seemed likely to be the kinase that phosphorylates TonEBP/OREBP because Y143 is in a consensus c-Abl phosphorylation site. We now confirm that, as follows. High NaCl increases c-Abl activity. Specific inhibition of c-Abl by imatinib, siRNA, or c-Abl kinase dead drastically reduces high NaCl-induced TonEBP/OREBP activity by reducing its nuclear location and transactivating activity. c-Abl associates with TonEBP/OREBP (coimmunoprecipitation) and phosphorylates TonEBP/OREBP-Y143 both in cell and in vitro. High NaCl-induced activation of ataxia telangiectasia mutated, previously known to contribute to activation of TonEBP/OREBP, depends on c-Abl activity. Thus, c-Abl is the kinase responsible for high NaCl-induced phosphorylation of TonEBP/OREBP-Y143, which contributes to its increased activity.--Gallazzini, M., Yu, M.-J., Gunaratne, R., Burg, M. B., Ferraris, J. D. c-Abl mediates high NaCl-induced phosphorylation and activation of the transcription factor TonEBP/OREBP.