cAMP/PKA-induced filamin A (FLNA) phosphorylation inhibits SST2 signal transduction in GH-secreting pituitary tumor cells

Peverelli, Erika; Giardino, Elena; Mangili, Federica; Treppiedi, Donatella; Catalano, Rosa; Ferrante, E.; Sala, Elisa; Locatelli, Marco; Lania, Andrea; Arosio, Maura; Spada, Anna; Mantovani, Giovanna

doi:10.1016/j.canlet.2018.08.002

Cited by 22 publications

(16 citation statements)

References 41 publications

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“…Caspase-3/7 enzymatic activity was measured using the Apo-ONE Homogenous Caspase-3/7 Assay (Promega, Madison, WI, USA) as previously described [20]. Briefly, MMQ cells were incubated with afuresertib 1, 5 or 10 μM, for 48 h.…”

Section: Apoptosis Assaymentioning

confidence: 99%

Beta-Arrestin 2 Is Required for Dopamine Receptor Type 2 Inhibitory Effects on AKT Phosphorylation and Cell Proliferation in Pituitary Tumors

et al. 2020

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Dopamine receptor type 2 (DRD2) agonists are the first-choice treatment for prolactin-secreting pituitary tumors but are poorly effective in nonfunctioning pituitary neuroendocrine tumors (NF-PitNETs). DRD2 reduces AKT phosphorylation in lactotrophs, but no data are available in NF-PitNETs. DRD2 effects on AKT are mediated by a β-arrestin 2-dependent mechanism in mouse striatum. The aim of this study was to investigate DRD2 effects on AKT phosphorylation and cell proliferation in human primary cultured NF-PitNET cells and in rat tumoral lactotroph cells MMQ, and to test β-arrestin 2 involvement. We found that the DRD2 agonist BIM53097 induced a reduction of the p-AKT/total-AKT ratio in MMQ (–32.8 ± 17.6%, <i>p</i> < 0.001 vs. basal) and in a subset (<i>n</i> = 15/41, 36.6%) of NF-PitNETs (subgroup 1). In the remaining NF-PitNETs (subgroup 2), BIM53097 induced an increase in p-AKT. The ability of BIM53097 to reduce p-AKT correlated with its antimitotic effect, since the majority of subgroup 1 NF-PitNETs was responsive to BIM53097, and nearly all subgroup 2 NF-PitNETs were resistant. β-Arrestin 2 was expressed in MMQ and in 80% of subgroup 1 NF-PitNETs, whereas it was undetectable in 77% of subgroup 2 NF-PitNETs. In MMQ, β-arrestin 2 silencing prevented DRD2 inhibitory effects on p-AKT and cell proliferation. Accordingly, β-arrestin 2 transfection in subgroup 2 NF-PitNETs conferred to BIM53097 the ability to inhibit both p-AKT and cell growth. In conclusion, we demonstrated that β-arrestin 2 is required for DRD2 inhibitory effects on AKT phosphorylation and cell proliferation in MMQ and NF-PitNETs, paving the way for a potential role of β-arrestin 2 as a biomarker predicting NF-PitNETs’ responsiveness to treatment with dopamine agonists.

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Section: Apoptosis Assaymentioning

confidence: 99%

Beta-Arrestin 2 Is Required for Dopamine Receptor Type 2 Inhibitory Effects on AKT Phosphorylation and Cell Proliferation in Pituitary Tumors

et al. 2020

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“…There are a large number of studies demonstrating the role of chaotic phosphorylation in the manifestation of tumors, including PitNETs [ 60 , 61 , 62 ]. Previous research has demonstrated that FLNA, an actin cross-linking protein, is the substrate of different phospho-kinases, and that it might prevent somatostatin receptor 2 (SST2) from regulating in GH-secreting pituitary tumor by means of being promoted by cAMP pathway and inhibited by somatostatin analogs (SSA) [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

“…About 538 known kinases are encoded in the human genome, and these counter mechanisms vastly improve the plasticity of the epigenome [ 18 ]. Recent developments in the understanding of the fundamental molecular mechanisms regarding cancer cell signaling have elucidated a vital role for kinases in the metastases and carcinogenesis of diverse types of cancer [ 9 , 54 , 55 , 63 ]. Since many protein kinases are associated with promoting cell proliferation, migration, and survival, when active or over-expressed, they are often involved in oncogenesis [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation-Mediated Molecular Pathway Changes in Human Pituitary Neuroendocrine Tumors Identified by Quantitative Phosphoproteomics

Wen

et al. 2021

Cells

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To investigate the biological role of protein phosphorylation in human nonfunctional pituitary neuroendocrine tumors (NF-PitNETs), proteins extracted from NF-PitNET and control tissues were analyzed with tandem mass tag (TMT)-based quantitative proteomics coupled with TiO2 enrichment of phosphopeptides. A total of 595 differentially phosphorylated proteins (DPPs) with 1412 phosphosites were identified in NF-PitNETs compared to controls (p < 0.05). KEGG pathway network analysis of 595 DPPs identified nine statistically significant signaling pathways, including the spliceosome pathway, the RNA transport pathway, proteoglycans in cancer, SNARE interactions in vesicular transport, platelet activation, bacterial invasion of epithelial cells, tight junctions, vascular smooth muscle contraction, and protein processing in the endoplasmic reticulum. GO analysis revealed that these DPPs were involved in multiple cellular components (CCs), biological processes (BPs), and molecule functions (MFs). The kinase analysis of 595 DPPs identified seven kinases, including GRP78, WSTF, PKN2, PRP4, LOK, NEK1, and AMPKA1, and the substrate of these kinases could provide new ideas for seeking drug targets for NF-PitNETs. The randomly selected DPP calnexin was further confirmed with immunoprecipitation (IP) and Western blot (WB). These findings provide the first DPP profiling, phosphorylation-mediated molecular network alterations, and the key kinase profiling in NF-PitNET pathogenesis, which are a precious resource for understanding the biological roles of protein phosphorylation in NF-PitNET pathogenesis and discovering effective phosphoprotein biomarkers and therapeutic targets and drugs for the management of NF-PitNETs.

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“…The authors demonstrated that the phosphomimetic S2152D FLNA mutant constitutively bound to SSTR2, but precluded inhibitory G proteins coupling to SSTR2, and completely abolished antiproliferative, pro-apoptotic and anti-migratory effects of selective SSTR2 activation by BIM23120 (Fig. 2) (Peverelli et al 2018b). In this scenario, phosphorylation seems to be a mechanism to switch FLNA function from a scaffold that allows SSTR2 signal transduction, to a signal termination protein that hampers all SSTR2 antitumoral effects (Fig.…”

Section: Flna Phosphorylationmentioning

confidence: 95%

“…Indeed, in both GH3 and GH4C1 cell lines and in primary cultured cells from GH-secreting pituitary tumors, forskolin increased, and SSTR2 agonist reduced, FLNA phosphorylation at S2152, with dramatic effects on FLNA binding to SSTR2 and SSTR2 signal transduction (Peverelli et al 2018b) (Fig. 2).…”

Section: Flna Phosphorylationmentioning

confidence: 95%

Cytoskeleton actin-binding proteins in clinical behavior of pituitary tumors

Mantovani

Treppiedi

Giardino

et al. 2019

Endocrine-Related Cancer

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Although generally benign, pituitary tumors are frequently locally invasive, with reduced success of neurosurgery and unresponsive to pharmacological treatment with somatostatin or dopamine analogues. The molecular basis of the different biological behavior of pituitary tumors are still poorly identified, but a body of work now suggests that the activity of specific cytoskeleton proteins is a key factor regulating both the invasiveness and drug resistance of these tumors. This review recapitulates the experimental evidence supporting a role for the actin-binding protein filamin A (FLNA) in the regulation of somatostatin and dopamine receptors expression and signaling in pituitary tumors, thus in determining the responsiveness to currently used drugs, somatostatin analogues and dopamine receptor type 2 agonists. Regarding the regulation of invasive behavior of pituitary tumoral cells, we bring evidence to the role of the actin-severing protein cofilin, whose activation status may be modulated by dopaminergic and somatostatinergic drugs, through FLNA involvement. Molecular mechanisms involved in the regulation of FLNA expression and function in pituitary tumors will also be discussed.

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cAMP/PKA-induced filamin A (FLNA) phosphorylation inhibits SST2 signal transduction in GH-secreting pituitary tumor cells

Cited by 22 publications

References 41 publications

Beta-Arrestin 2 Is Required for Dopamine Receptor Type 2 Inhibitory Effects on AKT Phosphorylation and Cell Proliferation in Pituitary Tumors

Beta-Arrestin 2 Is Required for Dopamine Receptor Type 2 Inhibitory Effects on AKT Phosphorylation and Cell Proliferation in Pituitary Tumors

Phosphorylation-Mediated Molecular Pathway Changes in Human Pituitary Neuroendocrine Tumors Identified by Quantitative Phosphoproteomics

Cytoskeleton actin-binding proteins in clinical behavior of pituitary tumors

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