SPRY2 loss enhances ErbB trafficking and PI3K/AKT signalling to drive human and mouse prostate carcinogenesis

Gao, Meiling; Patel, Rachana; Ahmad, Imran; Fleming, Janis; Edwards, Joanne; McCracken, Stuart; Sahadevan, Kanagasabai; Seywright, Morag; Norman, Jim C.; Sansom, Owen J.; Leung, Hing Y.

doi:10.1002/emmm.201100944

Cited by 44 publications

(57 citation statements)

References 40 publications

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“…Consistently, our data also showed that HER2, but not HER3, is involved in the heterodimerization with EGFR and in the regulation of EGF‐induced Akt signaling in HER2‐positive breast cancer cells. In support of our findings, the dominant role of HER2 but not HER3 in the ERK‐dependent EGFR internalization and Akt downregulation was found in prostate cancer and retinal pigment epithelial cells (Gao et al ., 2012; Garay et al ., 2015). These results suggest that the involvement of other members of HER kinase family in the ERK‐dependent feedback downregulation of EGFR and Akt signaling may be context specific (Hendriks et al ., 2003).…”

Section: Discussionmentioning

confidence: 99%

MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701

et al. 2017

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Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2‐positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase‐dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event. Furthermore, HER2 Thr701 was demonstrated as a direct phosphorylation target of ERK1/2. Inhibition of this specific phosphorylation prolonged the dimerization of HER2 with EGFR in a clathrin‐dependent manner, leading to the enhanced activation of HER2 and EGFR tyrosine kinase and their downstream Akt pathway. These results suggest that suppression of ERK‐mediated HER2 Thr701 phosphorylation contributes to MEK inhibitor‐induced Akt activation.

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Section: Discussionmentioning

confidence: 99%

MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701

et al. 2017

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“…15,34,[39][40][41][42][43] Chen et al have demonstrated that the promoter region of spry2 was only hypermethylated in a small fraction of the 55 CLL patients that were profiled, signifying alternate mechanisms that lead to Spry2 downregulation in CLL. 31 Interestingly, we identify SPRY2 as a direct target of miR-21 in human CLL cells.…”

Section: Discussionmentioning

confidence: 99%

Sprouty 2: a novel attenuator of B-cell receptor and MAPK-Erk signaling in CLL

Shukla¹,

Rai²,

Shukla³

et al. 2016

Blood

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Key Points• SPRY2 is downregulated in CLL cells from patients with poor prognosis. • SPRY2 is negative regulator of Syk-mediated BCR and MAPK-Erk signaling in CLL.Clinical heterogeneity is a major barrier to effective treatment of chronic lymphocytic leukemia (CLL). Emerging evidence suggests that constitutive activation of various signaling pathways like mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-Erk) signaling plays a role in the heterogeneous clinical outcome of CLL patients. In this study, we have investigated the role of Sprouty (SPRY)2 as a negative regulator of receptor and nonreceptor tyrosine kinase signaling in the pathogenesis of CLL. We show that SPRY2 expression is significantly decreased in CLL cells, particularly from poor-prognosis patients compared with those from good-prognosis patients. Overexpression of SPRY2 in CLL cells from poor-prognosis patients increased their apoptosis. Conversely, downregulation of SPRY2 in CLL cells from good-prognosis patients resulted in increased proliferation. Furthermore, CLL cells with low SPRY2 expression grew more rapidly in a xenograft model of CLL. Strikingly, B-cell-specific transgenic overexpression of spry2 in mice led to a decrease in the frequency of B1 cells, the precursors of CLL cells in rodents. Mechanistically, we show that SPRY2 attenuates the B-cell receptor (BCR) and MAPK-Erk signaling by binding to and antagonizing the activities of RAF1, BRAF, and spleen tyrosine kinase (SYK) in normal B cells and CLL cells. We also show that SPRY2 is targeted by microRNA-21, which in turn leads to increased activity of Syk and Erk in CLL cells. Taken together, these results establish SPRY2 as a critical negative regulator of BCR-mediated MAPK-Erk signaling in CLL, thereby providing one of the molecular mechanisms to explain the clinical heterogeneity of

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“…EGF Stimulation-Upon EGF binding, EGFR is involved in a series of trafficking events, including internalization, degradation, and recycling, which ultimately regulate its signal amplification and propagation (42). Also, integrins are known to regulate the trafficking of some membrane proteins (43).…”

Section: Expression Of Integrin ␣5 Delays Egfr Internalization Uponmentioning

confidence: 99%

Integrin α5 Suppresses the Phosphorylation of Epidermal Growth Factor Receptor and Its Cellular Signaling of Cell Proliferation via N-Glycosylation

Hang

Isaji

Hou

et al. 2015

Journal of Biological Chemistry

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SPRY2 loss enhances ErbB trafficking and PI3K/AKT signalling to drive human and mouse prostate carcinogenesis

Cited by 44 publications

References 40 publications

MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701

MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701

Sprouty 2: a novel attenuator of B-cell receptor and MAPK-Erk signaling in CLL

Integrin α5 Suppresses the Phosphorylation of Epidermal Growth Factor Receptor and Its Cellular Signaling of Cell Proliferation via N-Glycosylation

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