STANDARD_NAME	BIOCARTA_STRESS_PATHWAY
SYSTEMATIC_NAME	M9670
COLLECTION	C2:CP:BIOCARTA
MSIGDB_URL	https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/BIOCARTA_STRESS_PATHWAY
NAMESPACE	Human_RefSeq
DESCRIPTION_BRIEF	TNF/Stress Related Signaling
DESCRIPTION_FULL	TNF acts on several different signaling pathways through two cell surface receptors, TNFR1 and TNFR2 to regulate apoptotic pathways, NF-kB activation of inflammation, and activate stress-activated protein kinases (SAPKs). Interaction of TNFR1 with TRADD leads to activation of NF-kB and apoptosis pathways, while interaction with TRAF2 has generally been thought to be involved in stress kinase and NF-kB activation but is not required for TNF to induce apoptosis. Activation of NF-kB is mediated by TRAF2 through the NIK kinase and also by RIP but the observation that TNF activates NF-kB in mice lacking TRAF2 indicates that TRAF-2 does not play an essential role in this process. Stress-activated protein kinases, also called JNKs, are a family of map kinases activated by cellular stress and inflammatory signals. Binding of TNF to the TNFR1 receptor activates the germinal center kinase (GCK) through the TNF adaptor Traf2, activating the map kinase MEKK1. Both GCK and MEKK1 interact with Traf2, and GCK is required for MEKK1 activation by TNF, but GCK kinase activity does not appear to be required for MEKK1 activation. Instead, GCK activates MEKK1 by causing MEKK1 oligomerization and autophosphorylation. Tank increases the affinity of Traf2 for GCK to increase Map kinase activation by TNF. Once activated, MEKK1 stands at the top of a map kinase pathways leading to transcriptional regulation, including JNK phosphorylation of c-Jun to stimulate transcriptional activation by AP-1, a heterodimer of c-jun and fos or ATF proteins. The activation of the p38 Map kinase also contributes to AP-1 activation leading to the transcriptional activation of many stress and growth related genes. RIP has been suggested as a component of the p38 pathway in addition to playing a role in NF-kB activation. MEKK1 knockout mice support the role of MEKK1 in JNK activation in some cells but did not support MEKK1 dependent activation of NF-kB. Alternative redundant mechanisms may obscure the role of MEKK1 in NF-kB mechanisms. TNF activation of stress kinase pathways and downstream transcription factors may help to modulate the apoptotic pathways also activated by TNF.
PMID	
GEOID	
AUTHORS	
CONTRIBUTOR	BioCarta
CONTRIBUTOR_ORG	BioCarta
EXACT_SOURCE	
FILTERED_BY_SIMILARITY	
EXTERNAL_NAMES_FOR_SIMILAR_TERMS	
EXTERNAL_DETAILS_URL	https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_stressPathway.gif
SOURCE_MEMBERS	BM458535,NM_000594,NM_001065,NM_001099856,NM_001099857,NM_001145138,NM_001145255,NM_001165412,NM_001190720,NM_001199135,NM_001224,NM_001242778,NM_001243984,NM_001243985,NM_001278,NM_001315,NM_001556,NM_002228,NM_002750,NM_002756,NM_002758,NM_003010,NM_003639,NM_003789,NM_003804,NM_003805,NM_003954,NM_003998,NM_004180,NM_004579,NM_005171,NM_005921,NM_020529,NM_021138,NM_021975,NM_032982,NM_032983,NM_133484,NM_139012,NM_139013,NM_139014,NM_139046,NM_139047,NM_139049,NM_145109
GENE_SYMBOLS	,TNF,TNFRSF1A,IKBKG,IKBKG,RELA,IKBKG,NFKB1,IKBKB,TANK,CASP2,IKBKB,RELA,RELA,CHUK,MAPK14,IKBKB,JUN,MAPK8,MAP2K3,MAP2K6,MAP2K4,IKBKG,TRADD,RIPK1,CRADD,MAP3K14,NFKB1,TANK,MAP4K2,ATF1,MAP3K1,NFKBIA,TRAF2,RELA,CASP2,CASP2,TANK,MAPK14,MAPK14,MAPK14,MAPK8,,MAPK8,MAP2K3
FOUNDER_NAMES