{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nIGF1R is a multifunctional receptor that plays pivotal roles in normal physiology and organismal longevity. Experimental findings in mice have demonstrated that reduced IGF1R activity extends lifespan and enhances resistance to oxidative stress, and genetic variations in the IGF pathway are associated with human longevity. In addition, from invertebrates to vertebrates, IGF1R signaling is required for proper embryonic development and stem cell self‐renewal, while also mediating beneficial regenerative responses such as compensatory cardiac hypertrophy and renal repair via mesenchymal stem cell exosome transfer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, IGF1R is frequently upregulated or aberrantly activated, thereby driving cell proliferation, survival, transformation, invasion, and metastasis. Enhanced IGF1R signaling stimulates key downstream pathways—including PI3K/Akt and MAPK/ErK—that foster epithelial‐to‐mesenchymal transition and facilitate resistance to therapies such as anti‐EGFR agents, antiestrogens, and platinum‐based drugs. Moreover, crosstalk between IGF1R and other receptors (for example, the insulin receptor isoforms, TSH receptor, Notch, and hybrid receptor complexes) further amplifies oncogenic signals in diverse tumors, including glioblastoma, breast, thyroid‐associated, colon, ovarian, and prostate cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIGF1R signaling is tightly regulated at multiple levels by post‐translational modifications and by noncoding RNAs, which in turn influence both its activity and cellular localization. For example, autophosphorylation of conserved tyrosine residues—particularly Y1136—is crucial for efficient PI3K/Akt activation, and additional modifications such as SUMOylation promote nuclear translocation and gene‐activating functions. Furthermore, adaptor proteins like β‐arrestin recruit ubiquitin ligases (e.g., MDM2) to modulate receptor degradation. Several microRNAs (including miR‑148a/152, miR‑7, and miR‑122) have been shown to directly target IGF1R mRNA, thereby suppressing its expression and attenuating tumorigenic signaling. Building on these insights, selective IGF1R inhibitors (such as picropodophyllin, BMS‑754807, or dual IGF1R/insulin receptor inhibitors) are under investigation for their anticancer efficacy, with combinatorial approaches also showing promise in overcoming drug resistance. 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"}, {"type": "b", "children": [{"type": "t", "text": "Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2007-03-082586"}], "href": "https://doi.org/10.1182/blood-2007-03-082586"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17761519"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17761519"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Julie R McMullen, Tetsuo Shioi, Weei-Yuarn Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase(p110alpha) pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M310405200"}], "href": "https://doi.org/10.1074/jbc.M310405200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14597618"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14597618"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Susanna Tomasoni, Lorena Longaretti, Cinzia Rota, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Constitutively active type I insulin-like growth factor receptor causes transformation and xenograft growth of immortalized mammary epithelial cells and is accompanied by an epithelial-to-mesenchymal transition mediated by NF-kappaB and snail."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.01315-06"}], "href": "https://doi.org/10.1128/MCB.01315-06"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17296734"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17296734"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "X Zhao, W Dou, L He, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-7 functions as an anti-metastatic microRNA in gastric cancer by targeting insulin-like growth factor-1 receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2012.156"}], "href": "https://doi.org/10.1038/onc.2012.156"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22614005"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22614005"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Xiaoping Huang, Lizhi Gao, Shuiliang Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Heterotrimerization of the growth factor receptors erbB2, erbB3, and insulin-like growth factor-i receptor in breast cancer cells resistant to herceptin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-09-3321"}], "href": "https://doi.org/10.1158/0008-5472.CAN-09-3321"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20103628"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20103628"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Terry J Smith, Neil Hoa "}, {"type": "b", "children": [{"type": "t", "text": "Immunoglobulins from patients with Graves' disease induce hyaluronan synthesis in their orbital fibroblasts through the self-antigen, insulin-like growth factor-I receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2004-0716"}], "href": "https://doi.org/10.1210/jc.2004-0716"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15472208"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15472208"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "S T Guo, C C Jiang, G P Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-497 targets insulin-like growth factor 1 receptor and has a tumour suppressive role in human colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2012.214"}], "href": "https://doi.org/10.1038/onc.2012.214"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22710713"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22710713"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Yinghui Zhang, Marja Moerkens, Sreenivasa Ramaiahgari, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Breast Cancer Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/bcr2883"}], "href": "https://doi.org/10.1186/bcr2883"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21595894"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21595894"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Robert X Song, Christopher J Barnes, Zhenguo Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor alpha to the plasma membrane."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0308334100"}], "href": "https://doi.org/10.1073/pnas.0308334100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14764897"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14764897"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Adam Denley, Eric R Bonython, Grant W Booker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural determinants for high-affinity binding of insulin-like growth factor II to insulin receptor (IR)-A, the exon 11 minus isoform of the IR."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Endocrinol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/me.2004-0183"}], "href": "https://doi.org/10.1210/me.2004-0183"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15205474"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15205474"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Bhaumik B Patel, Radha Sengupta, Sadia Qazi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Curcumin enhances the effects of 5-fluorouracil and oxaliplatin in mediating growth inhibition of colon cancer cells by modulating EGFR and IGF-1R."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.23097"}], "href": "https://doi.org/10.1002/ijc.23097"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17918158"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17918158"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Deepali Sachdev, Julie S Hartell, Adrian V Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A dominant negative type I insulin-like growth factor receptor inhibits metastasis of human cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M305403200"}], "href": "https://doi.org/10.1074/jbc.M305403200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14615489"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14615489"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Yanmin Xu, Ji Huang, Leina Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-122 confers sorafenib resistance to hepatocellular carcinoma cells by targeting IGF-1R to regulate RAS/RAF/ERK signaling pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Lett (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.canlet.2015.11.034"}], "href": "https://doi.org/10.1016/j.canlet.2015.11.034"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26655273"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26655273"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Shin'ichi Miyamoto, Keiichi Yano, Seiji Sugimoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Matrix metalloproteinase-7 facilitates insulin-like growth factor bioavailability through its proteinase activity on insulin-like growth factor binding protein 3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.can-03-1916"}], "href": "https://doi.org/10.1158/0008-5472.can-03-1916"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14744783"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14744783"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Renato V Iozzo, Simone Buraschi, Marco Genua, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Decorin antagonizes IGF receptor I (IGF-IR) function by interfering with IGF-IR activity and attenuating downstream signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111.262766"}], "href": "https://doi.org/10.1074/jbc.M111.262766"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21840990"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21840990"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "A Rojas, G Liu, I Coleman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IL-6 promotes prostate tumorigenesis and progression through autocrine cross-activation of IGF-IR."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2010.605"}], "href": "https://doi.org/10.1038/onc.2010.605"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21258401"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21258401"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Ada Girnita, Leonard Girnita, Fabrizio del Prete, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.can-03-2522"}], "href": "https://doi.org/10.1158/0008-5472.can-03-2522"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14729630"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14729630"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "S Favelyukis, J H Till, S R Hubbard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure and autoregulation of the insulin-like growth factor 1 receptor kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Struct Biol (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nsb721"}], "href": "https://doi.org/10.1038/nsb721"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11694888"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11694888"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Joan M Carboni, Mark Wittman, Zheng Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer Ther (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1535-7163.MCT-09-0499"}], "href": "https://doi.org/10.1158/1535-7163.MCT-09-0499"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19996272"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19996272"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Daiana Vasilcanu, Ada Girnita, Leonard Girnita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The cyclolignan PPP induces activation loop-specific inhibition of tyrosine phosphorylation of the insulin-like growth factor-1 receptor. Link to the phosphatidyl inositol-3 kinase/Akt apoptotic pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1208065"}], "href": "https://doi.org/10.1038/sj.onc.1208065"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15334055"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15334055"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Bita Sehat, Ali Tofigh, Yingbo Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SUMOylation mediates the nuclear translocation and signaling of the IGF-1 receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Signal (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scisignal.2000628"}], "href": "https://doi.org/10.1126/scisignal.2000628"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20145208"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20145208"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Leonard Girnita, Ada Girnita, Olle Larsson "}, {"type": "b", "children": [{"type": "t", "text": "Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1431613100"}], "href": "https://doi.org/10.1073/pnas.1431613100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12821780"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12821780"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Leonard Girnita, Sudha K Shenoy, Bita Sehat, et al. "}, {"type": "b", "children": [{"type": "t", "text": "{beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M501129200"}], "href": "https://doi.org/10.1074/jbc.M501129200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15878855"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15878855"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Qing Xu, Yue Jiang, Yu Yin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A regulatory circuit of miR-148a/152 and DNMT1 in modulating cell transformation and tumor angiogenesis through IGF-IR and IRS1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Cell Biol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/jmcb/mjs049"}], "href": "https://doi.org/10.1093/jmcb/mjs049"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22935141"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22935141"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Yi Pan, Hongwei Liang, Huan Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Platelet-secreted microRNA-223 promotes endothelial cell apoptosis induced by advanced glycation end products via targeting the insulin-like growth factor 1 receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1301790"}], "href": "https://doi.org/10.4049/jimmunol.1301790"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24307738"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24307738"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Hind Medyouf, Samuel Gusscott, Hongfang Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20110121"}], "href": "https://doi.org/10.1084/jem.20110121"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21807868"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21807868"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Emily M Fox, Todd W Miller, Justin M Balko, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-11-1295"}], "href": "https://doi.org/10.1158/0008-5472.CAN-11-1295"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21908557"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21908557"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "S Eliasz, S Liang, Y Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Notch-1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2010.7"}], "href": "https://doi.org/10.1038/onc.2010.7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20154720"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20154720"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Tracy Criswell, Meghan Beman, Shinako Araki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Delayed activation of insulin-like growth factor-1 receptor/Src/MAPK/Egr-1 signaling regulates clusterin expression, a pro-survival factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M412569200"}], "href": "https://doi.org/10.1074/jbc.M412569200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15689620"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15689620"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Sven A Lang, Christian Moser, Andreas Gaumann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting heat shock protein 90 in pancreatic cancer impairs insulin-like growth factor-I receptor signaling, disrupts an interleukin-6/signal-transducer and activator of transcription 3/hypoxia-inducible factor-1alpha autocrine loop, and reduces orthotopic tumor growth."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-07-1104"}], "href": "https://doi.org/10.1158/1078-0432.CCR-07-1104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17975158"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17975158"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "José L San Millán, Marta Cortón, Gemma Villuendas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of the polycystic ovary syndrome with genomic variants related to insulin resistance, type 2 diabetes mellitus, and obesity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2003-031252"}], "href": "https://doi.org/10.1210/jc.2003-031252"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15181035"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15181035"}]}]}]}