Protein: Tribbles homolog 3 (TRB-3) (Neuronal cell death-inducible putative kinase) (SINK) (p65-interacting inhibitor of NF-kappa-B) (Q96RU7)
Organism: Homo sapiens (Human)
Function: Inactive protein kinase which acts as a regulator of the integrated stress response (ISR), a process for adaptation to various stress. Inhibits the transcriptional activity of DDIT3/CHOP and is involved in DDIT3/CHOP-dependent cell death during ER stress. May play a role in programmed neuronal cell death but does not appear to affect non-neuronal cells. Acts as a negative feedback regulator of the ATF4-dependent transcription during the ISR: while TRIB3 expression is promoted by ATF4, TRIB3 protein interacts with ATF4 and inhibits ATF4 transcription activity (By similarity). Disrupts insulin signaling by binding directly to Akt kinases and blocking their activation (By similarity). May bind directly to and mask the 'Thr-308' phosphorylation site in AKT1 (By similarity). Interacts with the NF-kappa-B transactivator p65 RELA and inhibits its phosphorylation and thus its transcriptional activation activity. Interacts with MAPK kinases and regulates activation of MAP kinases. Can inhibit APOBEC3A editing of nuclear DNA.
Subcellular location: Nucleus {ECO:0000269|PubMed:22977230}.
Sequence: MRATPLAAPAGSLSRKKRLELDDNLDTERPVQKRARSGPQPRLPPCLLPLSPPTAPDRATAVATASRLGPYVLLEPEEGGRAYQALHCPTGTEYTCKVYPVQEALAVLEPYARLPPHKHVARPTEVLAGTQLLYAFFTRTHGDMHSLVRSRHRIPEPEAAVLFRQMATALAHCHQHGLVLRDLKLCRFVFADRERKKLVLENLEDSCVLTGPDDSLWDKHACPAYVGPEILSSRASYSGKAADVWSLGVALFTMLAGHYPFQDSEPVLLFGKIRRGAYALPAGLSAPARCLVRCLLRREPAERLTATGILLHPWLRQDPMPLAPTRSHLWEAAQVVPDGLGLDEAREEEGDREVVLYG
InterPro domains: - IPR011009: Protein kinase-like domain superfamily (homologous_superfamily) [80-328]
- IPR024104: Pseudokinase tribbles family/serine-threonine-protein kinase 40 (family) [3-346]
- IPR000719: Protein kinase domain (domain) [68-315]
Interaction partners: - RAC-alpha serine/threonine-protein kinase
- Cyclic AMP-dependent transcription factor ATF-4
- Glutathione-specific gamma-glutamylcyclotransferase 1
- RAC-beta serine/threonine-protein kinase
- RIB43A-like with coiled-coils protein 2
- DNA damage-inducible transcript 3 protein
- Peroxisome proliferator-activated receptor alpha
- RAC-gamma serine/threonine-protein kinase
- E3 ubiquitin-protein ligase COP1
- Asparagine synthetase
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0005515 (protein binding)
Biological Process (BP): GO:0008150 (biological process), GO:0065007 (biological regulation), GO:0050789 (regulation of biological process), GO:0019222 (regulation of metabolic process), GO:0050794 (regulation of cellular process), GO:0009894 (regulation of catabolic process), GO:0060255 (regulation of macromolecule metabolic process), GO:0031323 (regulation of cellular metabolic process), GO:0080090 (regulation of primary metabolic process), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0019219 (regulation of nucleobase-containing compound metabolic process), GO:0051252 (regulation of RNA metabolic process), GO:0031329 (regulation of cellular catabolic process), GO:0042176 (regulation of protein catabolic process), GO:0051246 (regulation of protein metabolic process), GO:0061136 (regulation of proteasomal protein catabolic process), GO:2000058 (regulation of ubiquitin-dependent protein catabolic process), GO:0030162 (regulation of proteolysis), GO:1903050 (regulation of proteolysis involved in protein catabolic process), GO:0032434 (regulation of proteasomal ubiquitin-dependent protein catabolic process)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0031974 (membrane-enclosed lumen), GO:0005654 (nucleoplasm), GO:0043229 (intracellular organelle), GO:0043233 (organelle lumen), GO:0043227 (membrane-bounded organelle), GO:0043231 (intracellular membrane-bounded organelle), GO:0070013 (intracellular organelle lumen), GO:0031981 (nuclear lumen), GO:0005634 (nucleus)