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All rights reserved. http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://purl.org/dc/elements/1.1/title BEL Framework Large Corpus Document http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://purl.org/pav/authoredBy http://www.tkuhn.ch/bel2nanopub/RA9ajR49A3CBfsII14LXVGyvxtBdAhKE6-RZ31ZNToePU#_7 http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://purl.org/pav/version 20131211 http://www.tkuhn.ch/bel2nanopub/RA9ajR49A3CBfsII14LXVGyvxtBdAhKE6-RZ31ZNToePU#_6 http://www.w3.org/ns/prov#value To explore this further, we have blocked endogenous ErbB3 transcription, thereby engineering tumor cells with overexpressed, fully active ErbB2 but lacking ErbB3 (T. Holbro and N.E. Hynes, unpublished data). As a consequence, these cells have decreased PI-3K/PKB signaling, a reduction in D-type cyclin levels, and show an increase in the G1 phase of the cell cycle. A main effector of ErbB signaling, the PI-3K/PKB pathway, is particularly important in mediating cell survival 103 T. Holbro et al. / Experimental Cell Research 284 (2003) 99-110 since several PKB substrates directly control various apoptotic processes. The proapoptotic Bcl family member Bad, when phosphorylated by PKB [93], is retained in the cytosol where it is unable to inhibit survival proteins like Bcl-XL on the mitochondria [94]. In normal mammary cells, blocking ErbB1 activity leads to apoptosis by lowering phospho-Bad levels, [95], a characteristic that would be extremely desirable to retain in cancer cells. Another PKB target is caspase-9, whose activation is blocked by phosphorylation [96] Members of the forkhead family of transcription factors, when phosphorylated by PKB, are retained in the cytoplasm and are unable to stimulate expression of several critical genes for apoptosis, including FasL, BIM, and others (reviewed by Brunet et al. [97]). Moreover, PKB phosphorylates IKK-alpha, which in turn inactivates IkappaB, thus leading to activation of NF-kappaB. This transcription factor upregulates levels of the prosurvival Bcl-XL protein and several inhibitors of apoptosis (IAPs) (reviewed by Datta et al. [98]). In this regard, it has been reported that cell lines overexpressing ErbB2 are resistant to TNF-induced apoptosis through a PKB/NF-B pathway [99]. Another ErbB effector protein, signal transducer, and activator of transcription (Stat) has been implicated in survival of squamous cell carcinomas of the head and neck. ErbB1, activated as a result of autocrine TGF-alpha expression in tumor cells, constitutively activates Stat3 [100]. Blocking Stat3 in vivo is associated with decreased level of the antiapoptotic Bcl-XL and increased tumor cell death [101]. http://www.tkuhn.ch/bel2nanopub/RA9ajR49A3CBfsII14LXVGyvxtBdAhKE6-RZ31ZNToePU#_6 http://www.w3.org/ns/prov#wasQuotedFrom http://www.ncbi.nlm.nih.gov/pubmed/12648469 http://www.tkuhn.ch/bel2nanopub/RA9ajR49A3CBfsII14LXVGyvxtBdAhKE6-RZ31ZNToePU#_7 http://www.w3.org/2000/01/rdf-schema#label Selventa http://www.tkuhn.ch/bel2nanopub/RA9ajR49A3CBfsII14LXVGyvxtBdAhKE6-RZ31ZNToePU#assertion http://www.w3.org/ns/prov#hadPrimarySource http://www.ncbi.nlm.nih.gov/pubmed/12648469 http://www.tkuhn.ch/bel2nanopub/RA9ajR49A3CBfsII14LXVGyvxtBdAhKE6-RZ31ZNToePU#assertion http://www.w3.org/ns/prov#wasDerivedFrom http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://www.tkuhn.ch/bel2nanopub/RA9ajR49A3CBfsII14LXVGyvxtBdAhKE6-RZ31ZNToePU#assertion http://www.w3.org/ns/prov#wasDerivedFrom http://www.tkuhn.ch/bel2nanopub/RA9ajR49A3CBfsII14LXVGyvxtBdAhKE6-RZ31ZNToePU#_6 http://www.tkuhn.ch/bel2nanopub/RA9ajR49A3CBfsII14LXVGyvxtBdAhKE6-RZ31ZNToePU#pubinfo http://www.tkuhn.ch/bel2nanopub/RA9ajR49A3CBfsII14LXVGyvxtBdAhKE6-RZ31ZNToePU http://purl.org/dc/terms/created 2014-07-03T14:32:00.319+02:00 http://www.tkuhn.ch/bel2nanopub/RA9ajR49A3CBfsII14LXVGyvxtBdAhKE6-RZ31ZNToePU http://purl.org/pav/createdBy http://orcid.org/0000-0001-6818-334X http://www.tkuhn.ch/bel2nanopub/RA9ajR49A3CBfsII14LXVGyvxtBdAhKE6-RZ31ZNToePU http://purl.org/pav/createdBy http://orcid.org/0000-0002-1267-0234