Identification of a Novel Mitogen-Inducible Gene (mig-6): Regulation during G1 Progression and Differentiation

Wick, Marilee J.; Bürger, Christiane; Funk, Martin; Müller, Rolf

doi:10.1006/excr.1995.1261

Cited by 64 publications

(51 citation statements)

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“…Whereas PARK7 is an oncogene that inhibits the PTEN tumor suppressor (25)(26)(27)), Mig-6 shows many properties consistent with a tumor suppressor role including cancer-prone phenotypes in knockout mice (12,13,28). In the context of this study, it is notable that Mig-6 was identified as a mitogen-inducible gene and is a presumed adaptor protein linked to the regulation of a variety of signaling pathways, including the key GBM oncogene EGFR (8)(9)(10)(11). This profile prompted us to assess the functional relevance of Mig-6 and determine its mechanism of action in GBM.…”

Section: Resultsmentioning

confidence: 91%

“…Here, using an integrated genomic and functional analysis, we have identified Mig-6 as a candidate tumor suppressor that regulates EGFR trafficking and turnover in GBM cells. Mig-6 was originally identified as a mitogen-inducible gene and has been implicated in the feedback regulation of a variety of signaling processes, including the EGFR pathway (8)(9)(10)(11). Ablation of Mig-6 was shown to induce tumor formation in various tissues, supporting the tumor suppressor function of .…”

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confidence: 94%

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Mig-6 controls EGFR trafficking and suppresses gliomagenesis

Ying

Zheng

Scott

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

107

123

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Glioblastoma multiforme (GBM) is the most common and lethal primary brain cancer that is driven by aberrant signaling of growth factor receptors, particularly the epidermal growth factor receptor (EGFR). EGFR signaling is tightly regulated by receptor endocytosis and lysosome-mediated degradation, although the molecular mechanisms governing such regulation, particularly in the context of cancer, remain poorly delineated. Here, high-resolution genomic profiles of GBM identified a highly recurrent focal 1p36 deletion encompassing the putative tumor suppressor gene, Mig-6. We show that Mig-6 quells the malignant potential of GBM cells and dampens EGFR signaling by driving EGFR into late endosomes and lysosome-mediated degradation upon ligand stimulation. Mechanistically, this effect is mediated by the binding of Mig-6 to a SNARE protein STX8, a protein known to be required for late endosome trafficking. Thus, Mig-6 functions to ensure recruitment of internalized receptor to late endosomes and subsequently the lysosomal degradation compartment through its ability to specifically link EGFR and STX8 during ligand-stimulated EGFR trafficking. In GBM, the highly frequent loss of Mig-6 would therefore serve to sustain aberrant EGFR-mediated oncogenic signaling. Together, these data uncover a unique tumor suppression mechanism involving the regulation of receptor trafficking.

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Section: Resultsmentioning

confidence: 91%

mentioning

confidence: 94%

Mig-6 controls EGFR trafficking and suppresses gliomagenesis

Ying

Zheng

Scott

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

107

123

View full text Add to dashboard Cite

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“…Mig-6 may provide a checkpoint for normal cell proliferation in certain tissues; disruption of Mig-6 leads to uncontrolled proliferation of cells as revealed by PCNA staining in gallbladder epithelium ( Figure 5) and in joint tissues (Zhang et al, 2005). A role for MIG-6 in cell cycle regulation has also been implied, as its expression is regulated during the normal cell cycle progression (Wick et al, 1995). Moreover, many stressful stimuli also induce the expression of Mig-6, which activates SAPK/JNK (Makkinje et al, 2000;Keeton and Messina, 2005).…”

Section: Discussionmentioning

confidence: 99%

Evidence that MIG-6 is a tumor-suppressor gene

et al. 2006

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“…Mig-6 is an immediate early response gene that can be induced by various mitogens and commonly occurring chronic stress stimuli (16)(17)(18). Mig-6 is an adaptor molecule containing a CRIB domain, a src homology 3 (SH3) binding domain, a 14-3-3 binding domain, and an epidermal growth factor receptor (EGFR) binding domain (19,20).…”

mentioning

confidence: 99%

Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease

Jeong

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

118

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Normal endometrial function requires a balance of progesterone (P4) and estrogen (E2) effects. An imbalance caused by increased E2 action and/or decreased P4 action can result in abnormal endometrial proliferation and, ultimately, endometrial adenocarcinoma, the fourth most common cancer in women. We have identified mitogen-inducible gene 6 (Mig-6) as a downstream target of progesterone receptor (PR) and steroid receptor coactivator (SRC-1) action in the uterus. Here, we demonstrate that absence of Mig-6 in mice results in the inability of P4 to inhibit E2-induced uterine weight gain and E2-responsive target genes expression. At 5 months of age, the absence of Mig-6 results in endometrial hyperplasia. Ovariectomized Mig-6 d/d mice exhibit this hyperplastic phenotype in the presence of E2 and P4 but not without ovarian hormone. Ovariectomized Mig-6 d/d mice treated with E2 developed invasive endometrioid-type endometrial adenocarcinoma. Importantly, the observation that endometrial carcinomas from women have a significant reduction in MIG-6 expression provides compelling support for an important growth regulatory role for Mig-6 in the uterus of both humans and mice. This demonstrates the Mig-6 is a critical regulator of the response of the endometrium to E2 in regulating tissue homeostasis. Since Mig-6 is regulated by both PR and SRC-1, this identifies a PR, SRC-1, Mig-6 regulatory pathway that is critical in the suppression of endometrial cancer.estrogen ͉ endometrial cancer ͉ progesterone ͉ progesterone receptor ͉ SRC-1

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Identification of a Novel Mitogen-Inducible Gene (mig-6): Regulation during G1 Progression and Differentiation

Cited by 64 publications

References 0 publications

Mig-6 controls EGFR trafficking and suppresses gliomagenesis

Mig-6 controls EGFR trafficking and suppresses gliomagenesis

Evidence that MIG-6 is a tumor-suppressor gene

Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease

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