Phosphorylation of threonine residues on Shc promotes ligand binding and mediates crosstalk between MAPK and Akt pathways in breast cancer cells

Suen, Kin Man; Lin, Chi-Chuan; Seiler, Caroline; George, Roger; Poncet-Montange, G.; Biter, Amadeo B.; Ahmed, Zamal; Arold, Stefan T.; Ladbury, John E.

doi:10.1016/j.biocel.2017.11.014

Cited by 10 publications

(10 citation statements)

References 48 publications

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“…Notably however, the pathways connecting SHC to PI3K, that are indicated by our current observations, remain unknown. Although several studies have suggested a complex formation occurs between SHC and PI3K via the 14-3-3 protein (Ursini-Siegel et al, 2012;Suen et al, 2018), it is not certain whether this underpinned any of our present findings. PI3K is one of the effectors of RAS (Vivanco and Sawyers, 2002;Castellano and Downward, 2011).…”

Section: Discussioncontrasting

confidence: 53%

“…It has been reported also that SHC is required for the full activation of RAS/MAPK signaling when cells are stimulated with growth factors at a low concentration (Lai and Pawson, 2000). In addition, SHC interacts with the complex of 14-3-3 and PI3K for activation of the RAS/MAPK and PI3K/AKT signaling pathways (Ursini-Siegel et al, 2012;Suen et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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p52Shc regulates the sustainability of ERK activation in a RAF-independent manner

Yoshizawa

Umeki

Yamamoto

et al. 2021

MBoC

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p52SHC (SHC) and GRB2 are adaptor proteins involved in the RAS/MAPK (ERK) pathway mediating signals from cell-surface receptors to various cytoplasmic proteins. To further examine their roles in signal transduction, we studied the translocation of fluorescently-labeled SHC and GRB2 to the cell surface, caused by the activation of ERBB receptors by heregulin (HRG). We simultaneously evaluated activated ERK translocation to the nucleus. Unexpectedly, the translocation dynamics of SHC were sustained when those of GRB2 were transient. The sustained localization of SHC positively correlated with the sustained nuclear localization of ERK, which became more transient after SHC knockdown. SHC-mediated PI3K activation was required to maintain the sustainability of the ERK translocation regulating MEK but not RAF. In cells overexpressing ERBB1, SHC translocation became transient, and the HRG-induced cell fate shifted from a differentiation to a proliferation bias. Our results indicate that SHC and GRB2 functions are not redundant, but that SHC plays the critical role in the temporal regulation of ERK activation.

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Section: Discussioncontrasting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

p52Shc regulates the sustainability of ERK activation in a RAF-independent manner

Yoshizawa

Umeki

Yamamoto

et al. 2021

MBoC

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“…Amino acids and acetate in cancers can be used as nutritional supports for protein synthesis and lipid metabolism, respectively. Threonine was reported to be responsible for Akt and ERK signalling pathway in breast cancer [14].…”

Section: Discussionmentioning

confidence: 99%

A biochemical comparison of the lung, colonic, brain, renal, and ovarian cancer cell lines using 1H-NMR spectroscopy

Liu

Zhao

et al. 2020

Bioscience Reports

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Cancer cell lines are often used for cancer research. However, continuous genetic instability-induced heterogeneity of cell lines can hinder the reproducibility of cancer research. Molecular profiling approaches including transcriptomics, chromatin modification profiling, and proteomics are used to evaluate the phenotypic characteristics of cell lines. However, these do not reflect the metabolic function at the molecular level. Metabolic phenotyping is a powerful tool to profile the biochemical composition of cell lines. In the present study, 1H-NMR spectroscopy-based metabolic phenotyping was used to detect metabolic differences among five cancer cell lines, namely, lung (A549), colonic (Caco2), brain (H4), renal (RCC), and ovarian (SKOV3) cancer cells. The concentrations of choline, creatine, lactate, alanine, fumarate and succinate varied remarkably among different cell types. The significantly higher intracellular concentrations of glutathione, myo-inositol, and phosphocholine were found in the SKOV3 cell line relative to other cell lines. The concentration of glutamate was higher in both SKOV3 and RCC cells compared with other cell lines. For cell culture media analysis, isopropanol was found to be the highest in RCC media, followed by A549 and SKOV3 media, while acetone was the highest in A549, followed by RCC and SKOV3. These results demonstrated that 1H-NMR-based metabolic phenotyping approach allows us to characterize specific metabolic signatures of cancer cell lines and provides phenotypical information of cellular metabolism.

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“…Specifically, the recruitment of PTP-PEST depends on Serine 29 phosphorylation to stabilize ShcA/PTP-PEST interactions. Moreover, Threonine 214 phosphorylation of ShcA was recently shown to increase ERK and AKT activation (49). Thus, serine/threonine phosphorylation of ShcA dynamically regulates the signaling potential of the adaptor protein, yet it is still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Integration of Distinct ShcA Signaling Complexes Promotes Breast Tumor Growth and Tyrosine Kinase Inhibitor Resistance

Ahn

Smith

et al. 2018

Molecular Cancer Research

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The commonality between most phospho-tyrosine signaling networks is their shared use of adaptor proteins to transduce mitogenic signals. ShcA () is one such adaptor protein that employs two phospho-tyrosine binding domains (PTB and SH2) and key phospho-tyrosine residues to promote mammary tumorigenesis. Receptor tyrosine kinases (RTK), such as ErbB2, bind the ShcA PTB domain to promote breast tumorigenesis by engaging Grb2 downstream of the ShcA tyrosine phosphorylation sites to activate AKT/mTOR signaling. However, breast tumors also rely on the ShcA PTB domain to bind numerous negative regulators that limit activation of secondary mitogenic signaling networks. This study examines the role of PTB-independent ShcA pools in controlling breast tumor growth and resistance to tyrosine kinase inhibitors. We demonstrate that PTB-independent ShcA complexes predominately rely on the ShcA SH2 domain to activate multiple Src family kinases (SFK), including Src and Fyn, in ErbB2-positive breast cancers. Using genetic and pharmacologic approaches, we show that PTB-independent ShcA complexes augment mammary tumorigenesis by increasing the activity of the Src and Fyn tyrosine kinases in an SH2-dependent manner. This bifurcation of signaling complexes from distinct ShcA pools transduces non-redundant signals that integrate the AKT/mTOR and SFK pathways to cooperatively increase breast tumor growth and resistance to tyrosine kinase inhibitors, including lapatinib and PP2. This study mechanistically dissects how the interplay between diverse intracellular ShcA complexes impacts the tyrosine kinome to affect breast tumorigenesis. The ShcA adaptor, within distinct signaling complexes, impacts tyrosine kinase signaling, breast tumor growth, and resistance to tyrosine kinase inhibitors. .

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Phosphorylation of threonine residues on Shc promotes ligand binding and mediates crosstalk between MAPK and Akt pathways in breast cancer cells

Cited by 10 publications

References 48 publications

p52Shc regulates the sustainability of ERK activation in a RAF-independent manner

p52Shc regulates the sustainability of ERK activation in a RAF-independent manner

A biochemical comparison of the lung, colonic, brain, renal, and ovarian cancer cell lines using 1H-NMR spectroscopy

Integration of Distinct ShcA Signaling Complexes Promotes Breast Tumor Growth and Tyrosine Kinase Inhibitor Resistance

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