Special Issue "Protein Phosphorylation in Cancer: Unraveling the Signaling Pathways"

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 30 November 2020.

Special Issue Editor

Dr. Peter Coopman
Website
Guest Editor
Institut de Recherche en Cancérologie de Montpellier/ INSERM U1194, CNRS, ICM, Univ. Montpellier, France
Interests: breast cancer; invasion and metastasis; tumor suppressors; tyrosine kinases; signaling networks; phospho-proteomics

Special Issue Information

Dear Colleagues,

The discovery of protein kinase key roles in cancer formation and progression has triggered great interest and stimulated intense research to develop pharmacological kinase inhibitors and therapeutic antibodies. These represent important steps in the development of targeted treatments, but also in the identification of prognostic and predictive biomarkers. Although the majority of efforts have been focused on tyrosine kinase inhibitors (TKI) and tyrosine kinase receptor (RTK)-targeting antibodies, renewed efforts and interests are being directed towards serine/threonine kinases and protein phosphatases.

Unfortunately, inhibitors often lack specificity and affect various kinases. In addition, treated tumors acquire drug resistance and relapse, requiring second-line treatments. With the advent of precision medicine, it is clear that networks are more robust biomarkers than individual proteins and genes. Drug development is moving to dynamic signaling network targeting. In the postgenomic era, post-translational modifications such as protein phosphorylation and how they affect activity or network architecture remain poorly understood. Current advances in (phospho)proteomic profiling allow complex signaling pathways to be unraveled. Bioinformatic modeling makes it possible to deal with the complex interactions between these pathways. It allows uncovering the difficultly discernable signaling cross-talks that positively and negatively affect tumor progression and that generate adaptive chemoresistance. To better cope with the tumor’s complexity, the application of new genetically-engineered and patient-derived xenograft murine models that more accurately mimic the genetic and biological evolution of human cancers makes it possible to design and test new targeted and specific therapeutic strategies.

With this open-access Special Issue on “Protein Phosphorylation in Cancer: Unraveling the Signaling Pathways”, we would like to provide an overview of the recent advances and cutting-edge approaches that allow better studying and understanding kinase/phosphatase signaling in tumor formation, progression, and drug resistance. Both original research articles and comprehensive reviews pertaining to a relevant topic within this vast and complex field are welcome.

We look forward to reading your contributions.

Dr. Peter Coopman
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer development and progression
  • protein kinases and phosphatases
  • targeted treatments and drug resistance
  • biomarker discovery
  • (phospho)proteomics
  • signal pathway reconstruction

Published Papers (3 papers)

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Research

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Open AccessFeature PaperArticle
The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer
Biomolecules 2020, 10(9), 1329; https://doi.org/10.3390/biom10091329 - 17 Sep 2020
Abstract
The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), [...] Read more.
The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS). TrkA was expressed in cancer epithelial and myoepithelial cells, with higher levels of TrkA positively associated with IDC (39% of cases) (p < 0.0001). Interestingly, TrkA was significantly increased in tumours expressing the human epidermal growth factor receptor-2 (HER2), with expression in 49% of HER2-positive compared to 25% of HER2-negative tumours (p = 0.0027). A panel of breast cancer cells were used to confirm TrkA protein expression, demonstrating higher levels of TrkA (total and phosphorylated) in HER2-positive cell lines. Functional investigations using four different HER2-positive breast cancer cell lines indicated that the Trk tyrosine kinase inhibitor GNF-5837 reduced cell viability, through decreased phospho-TrkA (Tyr490) and downstream AKT (Ser473) activation, but did not display synergy with Herceptin. Overall, these data highlight a relationship between the tyrosine kinase receptors TrkA and HER2 and suggest the potential of TrkA as a novel or adjunct target for HER2-positive breast tumours. Full article
(This article belongs to the Special Issue Protein Phosphorylation in Cancer: Unraveling the Signaling Pathways)
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Open AccessArticle
Activated Protein Kinase C (PKC) Is Persistently Trafficked with Epidermal Growth Factor (EGF) Receptor
Biomolecules 2020, 10(9), 1288; https://doi.org/10.3390/biom10091288 - 07 Sep 2020
Abstract
Protein kinase Cs (PKCs) are activated by lipids in the plasma membrane and bind to a scaffold assembled on the epidermal growth factor (EGF) receptor (EGFR). Understanding how this complex is routed is important, because this determines whether EGFR is degraded, terminating signaling. [...] Read more.
Protein kinase Cs (PKCs) are activated by lipids in the plasma membrane and bind to a scaffold assembled on the epidermal growth factor (EGF) receptor (EGFR). Understanding how this complex is routed is important, because this determines whether EGFR is degraded, terminating signaling. Here, cells were preincubated in EGF-tagged gold nanoparticles, then allowed to internalize them in the presence or absence of a phorbol ester PKC activator. PKC colocalized with EGF-tagged nanoparticles within 5 min and migrated with EGFR-bearing vesicles into the cell. Two conformations of PKC-epsilon were distinguished by different primary antibodies. One, thought to be enzymatically active, was on endosomes and displayed a binding site for antibody RR (R&D). The other, recognized by Genetex green (GG), was soluble, on actin-rich structures, and loosely bound to vesicles. During a 15-min chase, EGF-tagged nanoparticles entered large, perinuclear structures. In phorbol ester-treated cells, vesicles bearing EGF-tagged nanoparticles tended to enter this endocytic recycling compartment (ERC) without the GG form. The correlation coefficient between the GG (inactive) and RR conformations on vesicles was also lower. Thus, active PKC has a Charon-like function, ferrying vesicles to the ERC, and inactivation counteracts this function. The advantage conferred on cells by aggregating vesicles in the ERC is unclear. Full article
(This article belongs to the Special Issue Protein Phosphorylation in Cancer: Unraveling the Signaling Pathways)
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Review

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Open AccessFeature PaperReview
PP2A-B55 Holoenzyme Regulation and Cancer
Biomolecules 2020, 10(11), 1586; https://doi.org/10.3390/biom10111586 - 22 Nov 2020
Abstract
Protein phosphorylation is a post-translational modification essential for the control of the activity of most enzymes in the cell. This protein modification results from a fine-tuned balance between kinases and phosphatases. PP2A is one of the major serine/threonine phosphatases that is involved in [...] Read more.
Protein phosphorylation is a post-translational modification essential for the control of the activity of most enzymes in the cell. This protein modification results from a fine-tuned balance between kinases and phosphatases. PP2A is one of the major serine/threonine phosphatases that is involved in the control of a myriad of different signaling cascades. This enzyme, often misregulated in cancer, is considered a tumor suppressor. In this review, we will focus on PP2A-B55, a particular holoenzyme of the family of the PP2A phosphatases whose specific role in cancer development and progression has only recently been highlighted. The discovery of the Greatwall (Gwl)/Arpp19-ENSA cascade, a new pathway specifically controlling PP2A-B55 activity, has been shown to be frequently altered in cancer. Herein, we will review the current knowledge about the mechanisms controlling the formation and the regulation of the activity of this phosphatase and its misregulation in cancer. Full article
(This article belongs to the Special Issue Protein Phosphorylation in Cancer: Unraveling the Signaling Pathways)
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