The ShcA SH2 domain engages a 14-3-3/PI3′K signaling complex and promotes breast cancer cell survival

Ursini‐Siegel, Josie; Hardy, W. Rod; Zheng, Yong; Chen, Ling; Zuo, Dongmei; Zhang, C; Podmore, Lauren; Pawson, Tony; Muller, William J.

doi:10.1038/onc.2012.4

Cited by 19 publications

(29 citation statements)

References 43 publications

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“…Because Gab adapter family are known to recruit the PI3K signaling pathway (35,40), this could allow sustained recruitment of Gab-1 that indirectly activates the PI3K signaling. Consistent with the importance of adapter proteins as scaffolds involved in PI3K signaling, we recently showed that the SH2 domain of the ShcA adapter can activate the PI3K signaling pathway through a multiprotein complex comprising ShcA, 14-3-3z, and the p85 regulatory subunit of PI3K (41). Given that ErbB2 can recruit the ShcA through multiple tyrosine docking sites (42), the robust ErbB2/PI3K signaling activity observed in ErbB2/ ErbB3 D85 tumors (Fig.…”

Section: D85mentioning

confidence: 71%

Uncoupling of PI3K from ErbB3 Impairs Mammary Gland Development but Does Not Impact on ErbB2-Induced Mammary Tumorigenesis

et al. 2012

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The formation of ErbB2/ErbB3 heterodimers plays a critical role in ErbB2-mediated signaling in both normal mammary development and mammary tumor progression. Through 7 phosphoinositide 3-kinase (PI3K) phosphotyrosine-binding sites, ErbB3 is able to recruit PI3K and initiate the PI3K/AKT signaling pathway. To directly explore the importance of the ErbB3/PI3K pathway in mammary development and tumorigenesis, we generated a mouse model that carries a mutant ErbB3 allele lacking the seven known PI3K-binding sites (ErbB3 ). Mice homozygous for the ErbB3 D85 allele exhibited an initial early growth defect and a dramatic impairment of mammary epithelial outgrowth. Although homozygous adult mice eventually recovered from the growth defect, their mammary glands continued to manifest the mammary outgrowth and lactation defects throughout their adult life. Interestingly, despite the presence of a profound mammary gland defect, all of the female ErbB3D85 mice developed metastatic ErbB2-induced mammary tumors secondary to mammary epithelial expression of an activated ErbB2 oncogene capable of compensatory PI3K signaling from both EGF receptor and ErbB2. Our findings therefore indicate that, although ErbB3-associated PI3K activity is critical for mammary development, it is dispensable for ErbB2-induced mammary tumor progression. Cancer Res; 72(12); 3080-90. Ó2012 AACR.

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Section: D85mentioning

confidence: 71%

Uncoupling of PI3K from ErbB3 Impairs Mammary Gland Development but Does Not Impact on ErbB2-Induced Mammary Tumorigenesis

et al. 2012

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“…In transgenic mouse models, deletion of all three ShcA isoforms in the mammary epithelium virtually ablates ErbB2-driven tumor induction (23,25). Using xenograft approaches, an important role for p46/52ShcA during mammary tumor growth, angiogenesis, and metastasis was shown (22,24,25). Our in vivo studies provide the first experimental evidence that p66ShcA contributes to tumor heterogeneity in luminal breast cancers by inducing an EMT.…”

Section: ϫ8mentioning

confidence: 73%

“…While it is well established that the p46/52ShcA isoforms are critical for breast cancer progression (22)(23)(24)(25), the biological significance of p66ShcA during this process is poorly understood. We provide the first experimental evidence that p66ShcA is a major driver of breast cancer plasticity, both in vitro and in vivo, by inducing an epithelial-to-mesenchymal transition.…”

mentioning

confidence: 99%

p66ShcA Promotes Breast Cancer Plasticity by Inducing an Epithelial-to-Mesenchymal Transition

Hudson

Sabourin

et al. 2014

Molecular and Cellular Biology

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dBreast cancers are stratified into distinct subtypes, which influence therapeutic responsiveness and patient outcome. Patients with luminal breast cancers are often associated with a better prognosis relative to that with other subtypes. However, subsets of patients with luminal disease remain at increased risk of cancer-related death. A critical process that increases the malignant potential of breast cancers is the epithelial-to-mesenchymal transition (EMT). The p66ShcA adaptor protein stimulates the formation of reactive oxygen species in response to stress stimuli. In this paper, we report a novel role for p66ShcA in inducing an EMT in HER2؉ luminal breast cancers. p66ShcA increases the migratory properties of breast cancer cells and enhances signaling downstream of the Met receptor tyrosine kinase in these tumors. Moreover, Met activation is required for a p66ShcA-induced EMT in luminal breast cancer cells. Finally, elevated p66ShcA levels are associated with the acquisition of an EMT in primary breast cancers spanning all molecular subtypes, including luminal tumors. This is of high clinical relevance, as the luminal and HER2 subtypes together comprise 80% of all newly diagnosed breast cancers. This study identifies p66ShcA as one of the first prognostic biomarkers for the identification of more aggressive tumors with mesenchymal properties, regardless of molecular subtype.

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“…Transgenic and orthotopic mouse models of ErbB2-and Polyoma Virus MT antigen-driven breast cancer show that these tyrosine residues transduce critical and nonoverlapping signals to promote breast cancer progression (4). Transgenic studies in MMTV/MT mice further show an important role for the ShcA SH2 domain in promoting breast cancer cell survival by engaging a 14-3-3/phospoinositide-3 kinase (PI3K) signaling complex at the plasma membrane (11).…”

Section: Introductionmentioning

confidence: 99%

“…Paraffin-embedded sections were also subjected to TUNEL staining (Apoptag Detection Kit, Chemicon) according to the manufacturer's instructions. CD31 (1:250; 550274, BD Biosciences) and F4/80 (1:250; MF48004-3, Invitrogen) staining was carried out on OCT-embedded sections as previously described (11). Slides were scanned using a ScanScope XT Digital Slide Scanner (Aperio) and data was analyzed with positive pixel count or nuclear algorithms.…”

Section: Immunohistochemistrymentioning

confidence: 99%

The ShcA PTB Domain Functions as a Biological Sensor of Phosphotyrosine Signaling during Breast Cancer Progression

Ahn

Sabourin

et al. 2013

Cancer Research

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ShcA (SHC1) is an adapter protein that possesses an SH2 and a PTB phosphotyrosine-binding motif. ShcA generally uses its PTB domain to engage activated receptor tyrosine kinases (RTK), but there has not been a definitive determination of the role of this domain in tumorigenesis. To address this question, we employed a ShcA mutant (R175Q) that no longer binds phosphotyrosine residues via its PTB domain. Here, we report that transgenic expression of this mutant delays onset of mammary tumors in the MMTV-PyMT mouse model of breast cancer. Paradoxically, we observed a robust increase in the growth and angiogenesis of mammary tumors expressing ShcR175Q, which displayed increased secretion of fibronectin and expression of integrin a5/b1, the principal fibronectin receptor. Sustained integrin engagement activated Src, which in turn phosphorylated proangiogenic RTKs, including platelet-derived growth factor receptor, fibroblast growth factor receptor, and Met, leading to increased VEGF secretion from ShcR175Q-expressing breast cancer cells. We defined a ShcR175Q-dependent gene signature that could stratify breast cancer patients with a high microvessel density. This study offers the first in vivo evidence of a critical role for intracellular signaling pathways downstream of the ShcA PTB domain, which both positively and negatively regulate tumorigenesis during various stages of breast cancer progression. Cancer Res; 73(14); 4521-32. Ó2013 AACR.

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The ShcA SH2 domain engages a 14-3-3/PI3′K signaling complex and promotes breast cancer cell survival

Cited by 19 publications

References 43 publications

Uncoupling of PI3K from ErbB3 Impairs Mammary Gland Development but Does Not Impact on ErbB2-Induced Mammary Tumorigenesis

Uncoupling of PI3K from ErbB3 Impairs Mammary Gland Development but Does Not Impact on ErbB2-Induced Mammary Tumorigenesis

p66ShcA Promotes Breast Cancer Plasticity by Inducing an Epithelial-to-Mesenchymal Transition

The ShcA PTB Domain Functions as a Biological Sensor of Phosphotyrosine Signaling during Breast Cancer Progression

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