PMC:4307189 / 37231-44220
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4307189","sourcedb":"PMC","sourceid":"4307189","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4307189","text":"Signaling cross-talk between EGFR/ErbB and other signaling pathways\n\nCross-talk between EGFR/ErbB and Notch signaling\nWe investigated literature evidence regarding the putative cross-talks between EGFR/ErbB signaling and other signaling pathways. We found AKT2:MAML2 (in Reactome and KEGG), AKT2:TP53 (in Reactome), AKT2:MYC (in Reactome), KIT:MAML2 (in Reactome), KIT:TP53 (in Reactome), MDM2:MAML2 (in Reactome and WikiPathway), MDM2:TP53 (in Reactome), and TP53:MAML2 (in WikiPathway) gene-pairs as putative cross-talks between EGFR/ErbB signaling and Notch signaling pathways. Up-regulation of the Notch signaling pathway inhibits apoptosis and thus contributes to breast carcinogenesis [37]. The Notch signaling pathway cross-talks with EGFR/ErbB signaling at the mediator level [1], e.g. when activated, Notch1 contributes to cell growth and survival via Akt-activation in melanoma [38]. The Notch1 co-activator complex binds to the HES1 promoter [39] which encodes a transcription repressor that represses the expression of PTEN, a PI3K/Akt pathway inhibitor [40] contributing to tyrosine kinase inhibitor (TKI) resistance. Furthermore, Notch1 stimulates MYC transcription [41] and this stimulation can lead to the down-regulation of MYC via the Akt-pathway [42,43]. This putative gene-pair, AKT2:MYC was also found in our results as a potential drug-resistant cross-talk between the EGFR/ErbB and TGF- β receptor signaling pathways. Again, in HER2/neu-mediated resistance to DNA-damaging agents, the Akt pathway becomes activated which eventually suppresses p53 functions via enhancing MDM2-mediated ubiquitination [44]. Protein-protein interaction between MDM2 and p53 is evident as contributing to various cancer related activities [45,46].\n\nCross-talk between EGFR/ErbB and Wnt signaling\nWe found MDM2:APC (in Reactome and WikiPathway), KIT:CDC73 (in Reactome), MDM2:CDC73 (in Reactome), CBL:APC (in Reactome and KEGG), PDGFRA:APC (in Reactome), and CBL:CDC73 (in Reactome), AKT2:APC (in KEGG), AKT2:TP53 (in KEGG), and TP53:APC (in WikiPathway) as putative drug-resistant cross-talks between EGFR/ErbB and Wnt signaling pathways. Deregulation of the Wnt/ β-catenin signaling pathway plays a critical role in various cancers including breast, colorectal, pancreatic and colon cancer [47,48], and its association with drug-resistance has been studied by several research groups [47-50]. Recently, it has been reported that resistant cell lines exhibited increased Wnt signaling in both breast and colon cancer [49,50]. Loh et al. showed that genes in the Wnt signaling pathway, in both the β-catenin dependent (AXIN2, MYC, CSNK1A1) and the independent arms (ROR2, JUN), were up-regulated in cell lines resistant to tamoxifen compared to the parental MCF7 cell line [49]. Furthermore, ROR1, a constituent gene of Wnt signaling pathway, plays a sustainer role in EGFR-mediated prosurvival signaling in lung adenocarcinoma via signaling cross-talk and was therefore reported to be a potential therapeutic target [51]. APC and MDM2 in the MDM2:APC cross-talk are both tumor suppressors; they co-regulate DNA polymerase- β [52,53] which is reported to be hyper-activated in a cis-diamminedichloroplatinum(II) resistant P388 murine leukemia cell line [54]. Again, β-catenin whose stability is negatively regulated by APC [55], confers resistance to PI3K/Akt inhibitors in colon cancer [56].\n\nCross-talk between EGFR/ErbB and GPCR signaling\nBetween EGFR/ErbB and GPCR signaling pathways, we found KIT:GNAQ (in Reactome), MDM2:GNAQ (in Reactome and WikiPathway), CBL:GNAQ (in Reactome), FGFR2:GNAQ (in Reactome), PDGFRA:GNAQ (in Reactome), KIT:TSHR (in Reactome), MDM2:TSHR (in Reactome), CBL:TSHR (in Reactome), PDGFRA:TSHR (in Reactome), KIT:GNAS (in Reactome), MDM2:GNAS (in Reactome and WikiPathway), KIT:SMO (in Reactome), MDM2:SMO (in Reactome), TP53:GNAQ (in WikiPathway), and MYC:GNAQ (in WikiPathway). GPCR-like signaling contributes to acquired drug resistance after being mediated by Smoothened (SMO) via activating Gli, a canonical hedgehog (Hh) transcription factor [57]. GPCR and EGFR/ErbB over-expression often contributes to cancer growth. Cross-talk between the two at the receptor level contributes to HNSCC (head and neck squamous cell carcinoma) via triggering EGFR/ErbB signaling by a GPCR ligand [58]. For the MDM2:SMO cross-talk, found between the EGFR/ErbB and GPCR signaling pathways, a SMO-mutant from Hh signal transducer activates PI3K/Akt/Gli pathway that eventually increases MDM2 phosphorylation [59]. This in turn increases MDM2-mediated p53 degradation and thus reduces p53-induced apoptosis [59]. Furthermore, recently it has been reported that SMO (Hh signal transducer) functions like a G-protein coupled receptor due to its structural resemblance to GPCRs [60,61] which may be further evidence for a drug-resistant cross-talk between hedgehog signaling and EGFR/ErbB signaling [1].\n\nCross-talk between EGFR/ErbB and IR (insulin receptor)/IGF1R signaling\nSeveral studies have reported extensive cross-talk between IR (insulin receptor)/IGF1R (insulin-like growth factor-1 receptor) and EGFR/ErbB signaling pathways contributing to acquired drug resistance in various cancers [62-64]. Loduvini et al. reported significant correlation between worse disease-free survival and high co-expression of both EGFR/ErbB and IGF1R in NSCLC (non-small-cell lung cancer) patients [65]. EGFR/ErbB can physically interact with other non-ErbB family receptors at the cell surface and can form heterodimers with receptors like IGF1R, PDGFR etc. [62]. Moreover, the EGFR/ErbB and IGF1R pathways can also cross-talk indirectly via physical interactions between their downstream shared-components [62]. It has been reported recently that gefitinib (an EGFR TKI) inhibits the phosphorylation of IRS1 by IR, but also triggers the association between IRS1 and IGF1R which in turn induces drug-resistance [66]. Knowlden et al. showed the cross-talk between IGF1R and EGFR signaling pathways occurred in tamoxifen-resistant MCF7 and T47D breast cancer cell-lines but not in non-resistant cells [18]. Our findings suggest KIT:STK11 (in Reactome), MDM2:STK11 (in Reactome), MDM2:AKT2 (in WikiPathway), MYC:AKT2 (in WikiPathway), TP53:AKT2 (in WikiPathway), MDM2:CBL (in WikiPathway), MDM2:SOCS1 (in WikiPathway), and TP53:SOCS1 (in WikiPathway) as putative drug-resistant cross-talks between the IGF1R/IR and EGFR/ErbB signaling pathways. For the MDM2 and STK11 (also known as LKB1) genes, which we identified as a putative cross-talk between EGFR and IGF1R signaling, we did not find any direct supporting evidence in the literature. However, this association is plausible in the resistant conditions given that Yamaguchi et al. suggested EGFR signaling may cross-talk with the AMPK/LKB signaling pathway [1]. Moreover, Levine et al. reported interconnections between p53 and IGF1R/AKT/mTOR pathways where both LKB1 and MDM2 participate in a series of pathway cross-talks 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