Estrogen receptor binds IGF1R and SHC1 in response to estrogen

Stable Identifier
Reaction [omitted]
Homo sapiens
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Estrogen stimulates phosphorylation of the insulin-like growth factor 1 receptor (IGF1R) in a manner that depends on ESR1 but is independent of stimulation by the cognate IGF1 ligand (Richards et al, 1996; Richards et al, 1998; Kleinman et al, 1995; Lee et al, 1999; Kahlert et al, 2000; Song et al, 2002; Song et al, 2004). Estrogen-dependent phosphorylation of IGF1R depends on a physical interaction between the estrogen-bound estrogen receptor and IGF1R and may be promoted by SHC1 and SRC, although the molecular details are not established (Song et al, 2004). In one model, interaction of liganded ESR1 with SHC promotes the activation of SRC and active SRC then phosphorylates IGF1R at tyrosine residues required for SHC interaction. In this way, both SHC and liganded-ESR1 would be brought to IGF1R in a SRC-dependent manner. Consistent with this, SHC has been shown to activate SRC; however, this model has not been rigorously validated (Sato et al, 2002; Song et al, 2004). E2-stimulated IGF1R pathway activation also depends on activation of the MAPK pathway, as IGF1R phosphorylation is abrogated upon treatment of cells with MAPKK inhibitors (Kahlert et al, 2000; Song et al, 2004).
In addition to MAPK pathway activation, E2-dependent IGF1R activation promotes signaling through the EGFR pathway in a manner that depends on MMP2 and MMP9, suggesting that the cross-talk is mediated at the level of liberation of HBEGF from the plasma membrane (Song et al, 2004; Song et al, 2007, Santen et al, 2009). The details of this connection also remain to be fleshed out.

Literature References
PubMed ID Title Journal Year
8876252 Estradiol stimulates tyrosine phosphorylation of the insulin-like growth factor-1 receptor and insulin receptor substrate-1 in the uterus

Richards, RG, Clark, GC, Petrusz, P, DiAugustine, RP, Sebastian, J

Proc. Natl. Acad. Sci. U.S.A. 1996
19138696 Estrogen signals via an extra-nuclear pathway involving IGF-1R and EGFR in tamoxifen-sensitive and -resistant breast cancer cells

Fan, P, Yue, W, Song, RX, Bao, Y, Santen, RJ, Zhang, Z

Steroids 2009
11773443 Linkage of rapid estrogen action to MAPK activation by ERalpha-Shc association and Shc pathway activation

Song, RX, Kumar, R, Bao, Y, Santen, RJ, Shupnik, M, McPherson, RA, Adam, L

Mol. Endocrinol. 2002
12048194 Adaptor protein Shc is an isoform-specific direct activator of the tyrosine kinase c-Src

Fukami, Y, Sato, K, Iwasaki, T, Kakumoto, M, Tokmakov, AA, Kimoto, M, Owada, K, Nagao, T, Otsuki, T

J. Biol. Chem. 2002
14764897 The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor alpha to the plasma membrane

Song, RX, Kumar, R, Bao, Y, Santen, RJ, Zhang, Z, Barnes, CJ

Proc. Natl. Acad. Sci. U.S.A. 2004
10749889 Estrogen receptor alpha rapidly activates the IGF-1 receptor pathway

Vetter, H, Nuedling, S, Meyer, R, Grohe, C, Kahlert, S, van Eickels, M

J. Biol. Chem. 2000
17525128 Estrogen signaling via a linear pathway involving insulin-like growth factor I receptor, matrix metalloproteinases, and epidermal growth factor receptor to activate mitogen-activated protein kinase in MCF-7 breast cancer cells

Song, RX, Bao, Y, Santen, RJ, Zhang, Z, Chen, Y

Endocrinology 2007
10319328 Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo

Jackson, JG, Hilsenbeck, SG, Osborne, CK, Lee, AV, Coronado-Heinsohn, E, Gooch, JL, Yee, D

Mol. Endocrinol. 1999
7750475 Modulation of insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins in endometrial cancer cells by estradiol

Sharoni, Y, Segev, Y, Levy, J, LeRoith, D, Kleinman, D, Roberts, CT, Phillip, M, Karas, M

Endocrinology 1995
9565625 Insulin-like growth factor-1 (IGF-1) receptor-insulin receptor substrate complexes in the uterus. Altered signaling response to estradiol in the IGF-1(m/m) mouse

Richards, RG, DiAugustine, RP, Sebastian, J, Walker, MP

J. Biol. Chem. 1998
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