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Signal Transduction Pathways Involved in Regulation of Normal and Tumour Cells

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 25297

Special Issue Editor

Dr. Hedwig Sutterlüty-Fall

E-Mail Website
Guest Editor
Medical University of Vienna Institute of Cancer Research, Vienna, Austria
Interests: signal transduction; tumor biology; Sprouty proteins; posttranscriptional expression control

Special Issue Information

The human body consists of approximately 100,000 billion cells, necessitating their well-orchestrated interaction to guarantee proper functionality. An important form of intercellular communication functions via signalling cues released in the microenvironment. Subsequently, the entire autocrine and paracrine information in the approximate surrounding is converted to a cellular response. Disturbances in the multilayered network of signal transduction harm the cellular adjustment and result in diseases like cancer. Malignancy-inducing alterations in cancer cells frequently affect the intensity and duration of the transduced signals within the cell by striking molecules either directly involved in receiving and processing information or fulfilling a function as inhibitory and regulatory constraints of these processes.

In the Special Issue “Signal Transduction Pathways Involved in Regulation of Normal and Tumor Cells” we welcome manuscripts, either original work or review articles, focused on molecules or mechanisms involved in the transduction of signals.

Dr. Hedwig Sutterlüty-Fall
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 submissions that pass pre-check are 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • Signal transduction
  • Cancer
  • Receptor tyrosine kinase
  • Tumor microenvironment
  • Cell–cell communication
  • Signaling crosstalk

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Published Papers (6 papers)

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Editorial

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3 pages, 176 KiB  
Editorial
Signal Transduction as an Assimilation of Signals with Different Origins and Different Intracellular States
by Klaus Holzmann and Hedwig Sutterlüty
Int. J. Mol. Sci. 2023, 24(12), 10085; https://doi.org/10.3390/ijms241210085 - 13 Jun 2023
Cited by 2 | Viewed by 1230
Abstract
Higher organisms, such as humans, are made up of trillions of cells that have to act as a unit in a finely tuned way to ensure the functioning of the living being that is composed of them [...] Full article
(This article belongs to the Special Issue Signal Transduction Pathways Involved in Regulation of Normal and Tumour Cells)

Research

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27 pages, 6585 KiB  
Article
N-Linked Glycosylation in Chinese Hamster Ovary Cells Is Critical for Insulin-like Growth Factor 1 Signaling
by Rupashree Salvi, Chandan Kumar, Krupanshi Brahmbhatt, Rambhadur Subedi, Susan Idicula-Thomas, Taruna Madan and Barnali Biswas
Int. J. Mol. Sci. 2022, 23(23), 14952; https://doi.org/10.3390/ijms232314952 - 29 Nov 2022
Cited by 4 | Viewed by 2729
Abstract
Cell surface proteins carrying N-glycans play important roles in inter- and intracellular processes including cell adhesion, development, and cellular recognition. Dysregulation of the glycosylation machinery has been implicated in various diseases, and investigation of global differential cell surface proteome effects due to the [...] Read more.
Cell surface proteins carrying N-glycans play important roles in inter- and intracellular processes including cell adhesion, development, and cellular recognition. Dysregulation of the glycosylation machinery has been implicated in various diseases, and investigation of global differential cell surface proteome effects due to the loss of N-glycosylation will provide comprehensive insights into their pathogenesis. Cell surface proteins isolated from Parent Pro–5 CHO cells (W5 cells), two CHO mutants with loss of N-glycosylation function derived from Pro–5 CHO (Lec1 and Lec4 cells), were subjected to proteome analysis via high-resolution LCMS. We identified 44 and 43 differentially expressed membrane proteins in Lec1 and Lec4 cells, respectively, as compared to W5 cells. The defective N-glycosylation mutants showed increased abundance of integrin subunits in Lec1 and Lec4 cells at the cell surface. We also found significantly reduced levels of IGF-1R (Insulin like growth factor-1 receptor); a receptor tyrosine kinase; and the GTPase activating protein IQGAP1 (IQ motif-containing GTPase activating protein), a highly conserved cytoplasmic scaffold protein) in Lec1 and Lec4 cells. In silico docking studies showed that the IQ domain of IQGAP1 interacts with the kinase domain of IGF-1R. The integrin signaling and insulin growth factor receptor signaling were also enriched according to GSEA analysis and pathway analysis of differentially expressed proteins. Significant reductions of phosphorylation of ERK1 and ERK2 in Lec1 and Lec4 cells were observed upon IGF-1R ligand (IGF-1 LR3) stimulation. IGF-1 LR3, known as Long arginine3-IGF-1, is a synthetic protein and lengthened analog of insulin-like growth factor 1. The work suggests a novel mechanism for the activation of IGF-1 dependent ERK signaling in CHO cells, wherein IQGAP1 plausibly functions as an IGF-1R-associated scaffold protein. Appropriate glycosylation by the enzymes MGAT1 and MGAT5 is thus essential for processing of cell surface receptor IGF-1R, a potential binding partner in IQGAP1 and ERK signaling, the integral components of the IGF pathway. Full article
(This article belongs to the Special Issue Signal Transduction Pathways Involved in Regulation of Normal and Tumour Cells)
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17 pages, 3356 KiB  
Article
Sprouty3, but Not Sprouty1, Expression Is Beneficial for the Malignant Potential of Osteosarcoma Cells
by Anna Zita Mehira Kamptner, Christoph-Erik Mayer and Hedwig Sutterlüty
Int. J. Mol. Sci. 2021, 22(21), 11944; https://doi.org/10.3390/ijms222111944 - 4 Nov 2021
Cited by 1 | Viewed by 2142
Abstract
Sprouty proteins are widely accepted modulators of receptor tyrosine kinase-associated pathways and fulfill diversified roles in cancerogenesis dependent on the originating cells. In this study we detected a high expression of Sprouty3 in osteosarcoma-derived cells and addressed the question of whether Sprouty3 and [...] Read more.
Sprouty proteins are widely accepted modulators of receptor tyrosine kinase-associated pathways and fulfill diversified roles in cancerogenesis dependent on the originating cells. In this study we detected a high expression of Sprouty3 in osteosarcoma-derived cells and addressed the question of whether Sprouty3 and Sprouty1 influence the malignant phenotype of this bone tumor entity. By using adenoviruses, the Sprouty proteins were expressed in two different cell lines and their influence on cellular behavior was assessed. Growth curve analyses and Scratch assays revealed that Sprouty3 accelerates cell proliferation and migration. Additionally, more colonies were grown in Soft agar if the cells express Sprouty3. In parallel, Sprouty1 had no significant effect on the measured endpoints of the study in osteosarcoma-derived cells. The promotion of the tumorigenic capacities in the presence of Sprouty3 coincided with an increased activation of signaling as measured by evaluating the phosphorylation of extracellular signal-regulated kinases (ERKs). Ectopic expression of a mutated Sprouty3 protein, in which the tyrosine necessary for its activation was substituted, resulted in inhibited migration of the treated cells. Our findings identify Sprouty3 as a candidate for a tumor promoter in osteosarcoma. Full article
(This article belongs to the Special Issue Signal Transduction Pathways Involved in Regulation of Normal and Tumour Cells)
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13 pages, 3345 KiB  
Article
A Sprouty4 Mutation Identified in Kallmann Syndrome Increases the Inhibitory Potency of the Protein towards FGF and Connected Processes
by Astrid Stütz, Anna Z. M. Kamptner and Hedwig Sutterlüty
Int. J. Mol. Sci. 2021, 22(4), 2145; https://doi.org/10.3390/ijms22042145 - 21 Feb 2021
Cited by 5 | Viewed by 2877
Abstract
Kallmann syndrome is the result of innate genetic defects in the fibroblast growth factor (FGF) regulated signaling network causing diminished signal transduction. One of the rare mutations associated with the syndrome alters the Sprouty (Spry)4 protein by converting the serine at position 241 [...] Read more.
Kallmann syndrome is the result of innate genetic defects in the fibroblast growth factor (FGF) regulated signaling network causing diminished signal transduction. One of the rare mutations associated with the syndrome alters the Sprouty (Spry)4 protein by converting the serine at position 241 into a tyrosine. In this study, we characterize the tyrosine Spry4 mutant protein in the primary human embryonic lung fibroblasts WI-38 and osteosarcoma-derived cell line U2OS. As demonstrated in a cell signaling assay, Spry4 gains the capability of inhibiting FGF, but not epithelial growth factor (EGF)-induced signaling as a consequence of the tyrosine substitution. Additionally, migration of normal embryonic lung fibroblasts and osteosarcoma-derived cells is potently inhibited by the tyrosine Spry4 variant, while an effect of the wildtype Spry4 protein is hardly measureable. Concerning cell proliferation, the unaltered Spry4 protein is ineffective to influence the WI-38 cells, while the mutated Spry4 protein decelerates the cell doubling. In summary, these data emphasize that like the other mutations associated with Kallmann syndrome the described Spry4 mutation creates a hyperactive version of a selective inhibitory molecule and can thereby contribute to a weakened FGF signaling. Additionally, the study pinpoints a Spry4 variation expanding the applicability of Spry4 in a potential cancer therapy. Full article
(This article belongs to the Special Issue Signal Transduction Pathways Involved in Regulation of Normal and Tumour Cells)
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17 pages, 3781 KiB  
Article
3D Bone Morphology Alters Gene Expression, Motility, and Drug Responses in Bone Metastatic Tumor Cells
by Ushashi C. Dadwal, Alyssa R. Merkel, Jonathan M. Page, Kristin A. Kwakwa, Michael Kessler and Julie A. Rhoades
Int. J. Mol. Sci. 2020, 21(18), 6913; https://doi.org/10.3390/ijms21186913 - 21 Sep 2020
Cited by 6 | Viewed by 3056
Abstract
Patients with advanced skeletal metastases arising from primary cancers including breast, lung, and prostate suffer from extreme pain, bone loss, and frequent fractures. While the importance of interactions between bone and tumors is well-established, our understanding of complex cell–cell and cell–microenvironment interactions remains [...] Read more.
Patients with advanced skeletal metastases arising from primary cancers including breast, lung, and prostate suffer from extreme pain, bone loss, and frequent fractures. While the importance of interactions between bone and tumors is well-established, our understanding of complex cell–cell and cell–microenvironment interactions remains limited in part due to a lack of appropriate 3D bone models. To improve our understanding of the influence of bone morphometric properties on the regulation of tumor-induced bone disease (TIBD), we utilized bone-like 3D scaffolds in vitro and in vivo. Scaffolds were seeded with tumor cells, and changes in cell motility, proliferation, and gene expression were measured. Genes associated with TIBD significantly increased with increasing scaffold rigidity. Drug response differed when tumors were cultured in 3D compared to 2D. Inhibitors for Integrin β3 and TGF-β Receptor II significantly reduced bone-metastatic gene expression in 2D but not 3D, while treatment with the Gli antagonist GANT58 significantly reduced gene expression in both 2D and 3D. When tumor-seeded 3D scaffolds were implanted into mice, infiltration of myeloid progenitors changed in response to pore size and rigidity. This study demonstrates a versatile 3D model of bone used to study the influence of mechanical and morphometric properties of bone on TIBD. Full article
(This article belongs to the Special Issue Signal Transduction Pathways Involved in Regulation of Normal and Tumour Cells)
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Review

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55 pages, 3450 KiB  
Review
The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs
by Dexter L. Puckett, Mohammed Alquraishi, Winyoo Chowanadisai and Ahmed Bettaieb
Int. J. Mol. Sci. 2021, 22(3), 1171; https://doi.org/10.3390/ijms22031171 - 25 Jan 2021
Cited by 54 | Viewed by 12155
Abstract
Pyruvate kinase is a key regulator in glycolysis through the conversion of phosphoenolpyruvate (PEP) into pyruvate. Pyruvate kinase exists in various isoforms that can exhibit diverse biological functions and outcomes. The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through [...] Read more.
Pyruvate kinase is a key regulator in glycolysis through the conversion of phosphoenolpyruvate (PEP) into pyruvate. Pyruvate kinase exists in various isoforms that can exhibit diverse biological functions and outcomes. The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through the regulation of key signaling pathways. In cancer cells, the dimer form of PKM2 predominates and plays an integral role in cancer metabolism. This predominance of the inactive dimeric form promotes the accumulation of phosphometabolites, allowing cancer cells to engage in high levels of synthetic processing to enhance their proliferative capacity. PKM2 has been recognized for its role in regulating gene expression and transcription factors critical for health and disease. This role enables PKM2 to exert profound regulatory effects that promote cancer cell metabolism, proliferation, and migration. In addition to its role in cancer, PKM2 regulates aspects essential to cellular homeostasis in non-cancer tissues and, in some cases, promotes tissue-specific pathways in health and diseases. In pursuit of understanding the diverse tissue-specific roles of PKM2, investigations targeting tissues such as the kidney, liver, adipose, and pancreas have been conducted. Findings from these studies enhance our understanding of PKM2 functions in various diseases beyond cancer. Therefore, there is substantial interest in PKM2 modulation as a potential therapeutic target for the treatment of multiple conditions. Indeed, a vast plethora of research has focused on identifying therapeutic strategies for targeting PKM2. Recently, targeting PKM2 through its regulatory microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) has gathered increasing interest. Thus, the goal of this review is to highlight recent advancements in PKM2 research, with a focus on PKM2 regulatory microRNAs and lncRNAs and their subsequent physiological significance. Full article
(This article belongs to the Special Issue Signal Transduction Pathways Involved in Regulation of Normal and Tumour Cells)
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