c-Abl mediates high NaCl-induced phosphorylation and activation of the transcription factor TonEBP/OREBP.
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
Morgan
M
Laboratory of Kidney and Electrolyte Metabolism, National Heart Lung and Blood Institute, Bethesda, MD 20892-1603, USA.gallazzinim@gmail.com
Yu
Ming-Jiun
MJ
Gunaratne
Ruwan
R
Burg
Maurice B
MB
Ferraris
Joan D
JD
D000595:Amino Acid Sequence; D000818:Animals; D001549:Benzamides; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000068877:Imatinib Mesylate; D007679:Kidney Medulla / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D021381:Protein Transport / Q000502:physiology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016415:Sequence Alignment; D012965:Sodium Chloride / Q000494:pharmacology; D015533:Transcriptional Activation / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
D001549:Benzamides; D050778:NFATC Transcription Factors; D010879:Piperazines; D011743:Pyrimidines; D014443:Tyrosine; D012965:Sodium Chloride; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl