Protein kinase D induces transcription through direct phosphorylation of the cAMP-response element-binding protein.
Protein kinase D (PKD), a family of serine/threonine kinases, can be activated by a multitude of stimuli in a protein kinase C-dependent or -independent manner. PKD is involved in signal transduction pathways controlling cell proliferation, apoptosis, motility, and protein trafficking. Despite its versatile functions, few genuine in vivo substrates for PKD have been identified. In this study we demonstrate that the transcription factor cAMP-response element-binding protein (CREB) is a direct substrate for PKD. PKD1 and CREB interact in cells, and activated PKD1 provokes CREB phosphorylation at Ser-133 both in vitro and in vivo. A constitutive active mutant of PKD1 stimulates GAL4-CREB-mediated transcription in a Ser-133-dependent manner, activates CRE-responsive promoters, and increases the expression of CREB target genes. PKD1 also enhances transcription mediated by two other members of the CREB family, ATF-1 and CREM. Our results describe a novel mechanism for PKD-induced signaling through activation of the transcription factor CREB and suggest that stimulus-induced phosphorylation of CREB, reported to be mediated by protein kinase C, may involve downstream activated PKD.
Johannessen
Mona
M
Department of Microbiology and Virology, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway.
Delghandi
Marit Pedersen
MP
Rykx
An
A
Dragset
Marte
M
Vandenheede
Jackie R
JR
Van Lint
Johan
J
Moens
Ugo
U
D051697:Activating Transcription Factor 1; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D000071701:Regulatory Factor X Transcription Factors; D020218:Response Elements / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology*
C531110:ATF1 protein, human; D051697:Activating Transcription Factor 1; C115163:CREB1 protein, human; C497410:CREM protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D051786:Cyclic AMP Response Element Modulator; C089212:protein kinase D; D011493:Protein Kinase C