“Barcode” and Differential Effects of GPCR Phosphorylation by Different GRKs

Xiao, Kunhong; Liu, Hongda

doi:10.1007/978-1-4939-3798-1_5

Cited by 6 publications

(4 citation statements)

References 220 publications

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“…Post-translational modification has remained the focus of protein function investigation during the past decades, and phosphorylation is one of the most important modifications which we focused on [ 24 , 25 ]. Abnormal expression of kinases or phosphatases can result in dysregulated phosphorylation events, leading to various malignancies as we previously reported [ 14 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

SRPK1/2 and PP1α exert opposite functions by modulating SRSF1-guided MKNK2 alternative splicing in colon adenocarcinoma

Liu

Gong

et al. 2021

J Exp Clin Cancer Res

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Background The Mnk2 kinase, encoded by MKNK2 gene, plays critical roles in MAPK signaling and was involved in oncogenesis. Human MKNK2 pre-mRNA can be alternatively spliced into two splicing isoforms, the MKNK2a and MKNK2b, thus yielding Mnk2a and Mnk2b proteins with different domains. The involvement of Mnk2 alternative splicing in colon cancer has been implicated based on RNA-sequencing data from TCGA database. This study aimed at investigating the upstream modulators and clinical relevance of Mnk2 alternative splicing in colon adenocarcinoma (CAC). Methods PCR, western blotting and immunohistochemistry (IHC) were performed to assess the expression of Mnk2 and upstream proteins in CAC. The function of Mnk2 and its regulators were demonstrated in different CAC cell lines as well as in xenograft models. Two independent cohorts of CAC patients were used to reveal the clinical significance of MKNK2 alternative splicing. Results Comparing with adjacent nontumorous tissue, CAC specimen showed a decreased MKNK2a level and an increased MKNK2b level, which were correlated with KRAS mutation and tumor size. The SRSF1 (serine/arginine-rich splicing factor 1) was further confirmed to be the major splicing factor targeting MKNK2 in CAC cells. Higher expression of SRPK1/2 or decreased activity of PP1α were responsible for enhancing SRSF1 phosphorylation and nucleus translocation, subsequently resulted in a switch of MKNK2 alternative splicing. Conclusions Our data showed that phosphorylation and subcellular localization of SRSF1 were balanced by SRPK1/2 and PP1α in CAC cells. High nucleus SRSF1 promoted MKNK2 splicing into MKNK2b instead of MNK2a, consequently enhanced tumor proliferation.

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Section: Discussionmentioning

confidence: 99%

SRPK1/2 and PP1α exert opposite functions by modulating SRSF1-guided MKNK2 alternative splicing in colon adenocarcinoma

Liu

Gong

et al. 2021

J Exp Clin Cancer Res

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“…Phosphorylation and de-phosphorylation are one of the most important post-translational modifications in functional proteins. 7 Tyrosine phosphorylation is balanced by various kinases and protein tyrosine phosphatases (PTPs), playing critical roles in cellular survival, proliferation, and motility. PTPL1, also known as PTPN13, is a kind of non-receptor PTPs.…”

Section: Introductionmentioning

confidence: 99%

Protein tyrosine phosphatase L1 inhibits high-grade serous ovarian carcinoma progression by targeting IκBα

Wang

Huang

et al. 2018

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BackgroundHigh-grade serous ovarian cancer (HGSOC) represents most of the ovarian cancers and accounts for 70%–80 % of related deaths. The overall survival of HGSOC has not been remarkably improved in the past decades, due to the tumor dissemination in peritoneal cavity and invasion of adjacent organs. Therefore, identifying molecular biomarkers is invaluable in helping predicting clinical outcomes and developing targeted chemotherapies. Although there have been studies revealing the prognostic significance of protein tyrosine phosphatase L1 (PTPL1) in breast cancer and lung cancer, its involvement and functions in HGSOC remains to be elucidated.MethodsWe retrospectively enrolled a cohort of HGSOC patients after surgical resection. And analyzed the mRNA and protein levels of PTPL1 in tissue samples.ResultsWe found that PTPL1 presented a lower expression in HGSOC tissues than in adjacent normal ovarian tissues. Besides, the PTPL1 level was negatively correlated with tumor stage, implying its potential role as a tumor suppressor. Univariate and multivariate analyses identified that patients with higher PTPL1 showed a better overall survival compared to those with lower PTPL1 expression. In addition, cellular experiments confirmed the role of PTPL1 in suppressing tumor proliferation and invasion. Furthermore, we demonstrated that PTPL1 negatively regulated phosphorylation of tyrosine 42 on IκBα (IκBα-pY42). To our knowledge, this is the initial finding on PTPL1 targeting IκBα-pY42 site. Finally, our data indicated that PTPL1 suppressed tumor progression by dephosphorylating IκBα-pY42, which stabilized IκBα and attenuated nucleus translocation of NF-κB.ConclusionOur study revealed a tumor-suppressing role of PTPL1 in HGSOC by targeting IκBα.

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“…The post-translational modifications of ECT2 also regulate its protein level and oncogenic functions, including ubiquitination [ 19 ] and phosphorylation [ 20 ]. As one of the most important post-translational modifications, phosphorylation plays critical roles in regulating signaling pathways [ 21 ]. Several phosphorylation sites on human ECT2 protein have been identified by mass spectrometry method, including Thr359, Ser367, Thr373, Ser376, Thr444, and Ser716 [ 22 – 24 ].…”

Section: Introductionmentioning

confidence: 99%

P53 and Protein Phosphorylation Regulate the Oncogenic Role of Epithelial Cell Transforming 2 (ECT2)

2017

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BackgroundGastric cancer (GC) is the second leading cause of cancer-related death worldwide, but little progress has been achieved in the treatment of advanced or metastatic GC. GC is highly heterogeneous and more studies are needed to elucidate the metastatic mechanisms. Epithelial cell transforming 2 (ECT2) has been reported to be up-regulated in GC tissues, but its signaling mechanisms remain unclear.Material/MethodsIn this study, we used Western blot analysis to compare the expression level of ECT2 in 2 GC cell lines: MKN1 and MKN45. Mutagenesis and transfections were conducted to investigate the oncogenic mechanisms of ECT2 in GC cells.ResultsECT2 was expressed at higher levels in MKN1 than in MKN45. Immunoblotting results showed that MKN1 expression was suppressed by p53-WT but was enhanced by p53-mutant. In addition, in vitro experiments showed that ECT2 positively regulated the proliferation and invasion of GC cells. To better explore the mechanisms of ECT2 in promoting GC progression, we introduced site-directed mutants of ECT2, and found that the phosphor-mimic mutant T359D enhanced its oncogenic activity. In contrast, activation of RhoA was inhibited in cells transfected with ECT2 phosphor-deficient mutant T359A. We found that the epithelial cell biomarker E-cadherin was down-regulated by ECT2-T359D, highlighting the role of phosphorylation in regulating epithelial-mesenchymal transition.ConclusionsOur results identified p53 as a novel up-stream signaling molecule of ECT2 in GC cells, and the post-translational modifications of ECT2 play important roles in regulating cancer development and progression.

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“Barcode” and Differential Effects of GPCR Phosphorylation by Different GRKs

Cited by 6 publications

References 220 publications

SRPK1/2 and PP1α exert opposite functions by modulating SRSF1-guided MKNK2 alternative splicing in colon adenocarcinoma

SRPK1/2 and PP1α exert opposite functions by modulating SRSF1-guided MKNK2 alternative splicing in colon adenocarcinoma

Protein tyrosine phosphatase L1 inhibits high-grade serous ovarian carcinoma progression by targeting IκBα

P53 and Protein Phosphorylation Regulate the Oncogenic Role of Epithelial Cell Transforming 2 (ECT2)

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“Barcode” and Differential Effects of GPCR Phosphorylation by Different GRKs

Cited by 6 publications

References 220 publications

SRPK1/2 and PP1α exert opposite functions by modulating SRSF1-guided MKNK2 alternative splicing in colon adenocarcinoma

SRPK1/2 and PP1α exert opposite functions by modulating SRSF1-guided MKNK2 alternative splicing in colon adenocarcinoma

Protein tyrosine phosphatase L1 inhibits high-grade serous ovarian carcinoma progression by targeting I&kappa;B&alpha;

P53 and Protein Phosphorylation Regulate the Oncogenic Role of Epithelial Cell Transforming 2 (ECT2)

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Protein tyrosine phosphatase L1 inhibits high-grade serous ovarian carcinoma progression by targeting IκBα