scholarly journals Identification of the Wallenda JNKKK as an Alk suppressor reveals increased competitiveness of Alk-expressing cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Georg Wolfstetter ◽  
Kathrin Pfeifer ◽  
Mattias Backman ◽  
Tafheem A. Masudi ◽  
Patricia Mendoza-García ◽  
...  
Keyword(s):  
Receptor Tyrosine Kinase ◽  
Leucine Zipper ◽  
Oncogenic Signaling ◽  
Human Neuroblastoma ◽  
Over Expression ◽  
Anaplastic Lymphoma ◽  
Multiple Loci ◽  
Wide Range ◽  
Oncogenic Driver ◽  
Suppressor Screen

Abstract Anaplastic lymphoma kinase (Alk) is a receptor tyrosine kinase of the insulin receptor super-family that functions as oncogenic driver in a range of human cancers such as neuroblastoma. In order to investigate mechanisms underlying Alk oncogenic signaling, we conducted a genetic suppressor screen in Drosophila melanogaster. Our screen identified multiple loci important for Alk signaling, including members of Ras/Raf/ERK-, Pi3K-, and STAT-pathways as well as tailless (tll) and foxo whose orthologues NR2E1/TLX and FOXO3 are transcription factors implicated in human neuroblastoma. Many of the identified suppressors were also able to modulate signaling output from activated oncogenic variants of human ALK, suggesting that our screen identified targets likely relevant in a wide range of contexts. Interestingly, two misexpression alleles of wallenda (wnd, encoding a leucine zipper bearing kinase similar to human DLK and LZK) were among the strongest suppressors. We show that Alk expression leads to a growth advantage and induces cell death in surrounding cells. Our results suggest that Alk activity conveys a competitive advantage to cells, which can be reversed by over-expression of the JNK kinase kinase Wnd.

scholarly journals Profiling Oncogenic Germline Mutations in Unselected Chinese Lung Cancer Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Jie Yang ◽  
Hefei Li ◽  
Ben Li ◽  
Wei Li ◽  
Qiang Guo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Cancer Patients ◽  
Germline Mutation ◽  
Receptor Tyrosine Kinase ◽  
Germline Mutations ◽  
Driver Genes ◽  
Lung Cancer Patients ◽  
Anaplastic Lymphoma ◽  
Oncogenic Driver

IntroductionEmerging evidence has suggested that inherited factors are also involved in lung cancer development. However, most studies focused on well-elucidated cancer predisposition genes, the majority of which are tumor suppressor genes. The profile of germline mutations in oncogenic driver genes remains unrevealed, which might also provide potential clinical implications for lung cancer management.MethodsSequencing data from 36,813 unselected lung cancer patients who underwent somatic mutation profiling were retrospectively reviewed. All recruited patients had matched white blood cell samples sequenced in parallel using a capture-based panel including eight key lung cancer driver genes (epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), MET proto-oncogene, receptor tyrosine kinase (MET), Kirsten rat sarcoma viral oncogene homolog (KRAS), Erb-B2 receptor tyrosine kinase 2(ERBB2), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), ret proto-oncogene (RET), and B-Raf proto-oncogene, serine/threonine kinase (BRAF)). Likely pathogenic/pathogenic (LP/P) variants were called according to the classification criteria of the American College of Medical Genetics and Genomics. Variants of uncertain significance (VUS) located in the kinase domains of driver genes and occurring recurrently (n ≥3) were also included for further analyses.ResultsSeven different LP/P variants in EGFR, MET, or RET were identified in 0.03% of lung cancer patients (n = 14) and 25 different VUS in the kinase domains of seven driver genes (except KRAS) were found with a prevalence of 0.3% (n = 117).Collectively, germline mutations were most frequently seen in ROS1 (n = 31, 0.084%), followed by MET (n = 23, 0.062%), EGFR (n = 22, 0.06%), ALK (n = 22, 0.06%) and RET (n = 17, 0.046%). LP/P variants and VUS fell the most commonly in EGFR (n = 10, 72%) and ROS1 (n = 31, 26%), respectively. Of the 10 patients with EGFR LP/P germline mutation, 70% also acquired somatic EGFR driver mutation exon21 p.L858R or exon19 deletion at baseline; while the three patients with pathogenic germline RET mutation displayed distinct baseline somatic profiles of rare EGFR mutation or KRAS exon2 p.G12C. We discovered 11 germline mutations that also occurred somatically, including four LP/P variants and seven VUS.ConclusionWe present the first study to systemically characterize the germline mutation in oncogenic driver genes in a large cohort of unselected patients with lung cancers.

scholarly journals Disruption of the HER3-PI3K-mTOR oncogenic signaling axis and PD-1 blockade as a multimodal precision immunotherapy in head and neck cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhiyong Wang ◽  
Yusuke Goto ◽  
Michael M. Allevato ◽  
Victoria H. Wu ◽  
Robert Saddawi-Konefka ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Head And Neck ◽  
Mtor Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Mtor Signaling ◽  
Wild Type ◽  
Oncogenic Signaling ◽  
Signaling Axis ◽  
Oncogenic Driver ◽  
Cancer Remission

AbstractImmune checkpoint blockade (ICB) therapy has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment, but <20% of patients achieve durable responses. Persistent activation of the PI3K/AKT/mTOR signaling circuitry represents a key oncogenic driver in HNSCC; however, the potential immunosuppressive effects of PI3K/AKT/mTOR inhibitors may limit the benefit of their combination with ICB. Here we employ an unbiased kinome-wide siRNA screen to reveal that HER3, is essential for the proliferation of most HNSCC cells that do not harbor PIK3CA mutations. Indeed, we find that persistent tyrosine phosphorylation of HER3 and PI3K recruitment underlies aberrant PI3K/AKT/mTOR signaling in PIK3CA wild type HNSCCs. Remarkably, antibody-mediated HER3 blockade exerts a potent anti-tumor effect by suppressing HER3-PI3K-AKT-mTOR oncogenic signaling and concomitantly reversing the immune suppressive tumor microenvironment. Ultimately, we show that HER3 inhibition and PD-1 blockade may provide a multimodal precision immunotherapeutic approach for PIK3CA wild type HNSCC, aimed at achieving durable cancer remission.

scholarly journals EphA2 and EGFR: Friends in Life, Partners in Crime. Can EphA2 Be a Predictive Biomarker of Response to Anti-EGFR Agents?

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 700
Author(s):  
Mario Cioce ◽  
Vito Michele Fazio
Keyword(s):  
Colorectal Cancer ◽  
Solid Tumors ◽  
Receptor Tyrosine Kinase ◽  
Predictive Biomarker ◽  
Eph Receptors ◽  
Oncogenic Signaling ◽  
Induced Stress ◽  
Molecular Determinants ◽  
Signaling Axis ◽  
Context Specific

The Eph receptors represent the largest group among Receptor Tyrosine kinase (RTK) families. The Eph/ephrin signaling axis plays center stage during development, and the deep perturbation of signaling consequent to its dysregulation in cancer reveals the multiplicity and complexity underlying its function. In the last decades, they have emerged as key players in solid tumors, including colorectal cancer (CRC); however, what causes EphA2 to switch between tumor-suppressive and tumor-promoting function is still an active theater of investigation. This review summarizes the recent advances in understanding EphA2 function in cancer, with detail on the molecular determinants of the oncogene-tumor suppressor switch function of EphA2. We describe tumor context-specific examples of EphA2 signaling and the emerging role EphA2 plays in supporting cancer—stem—cell-like populations and overcoming therapy-induced stress. In such a frame, we detail the interaction of the EphA2 and EGFR pathway in solid tumors, including colorectal cancer. We discuss the contribution of the EphA2 oncogenic signaling to the resistance to EGFR blocking agents, including cetuximab and TKIs.

scholarly journals Integrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma

2018 ◽  
Vol 11 (557) ◽  
pp. eaap9752 ◽  
Author(s):  
Kristina B. Emdal ◽  
Anna-Kathrine Pedersen ◽  
Dorte B. Bekker-Jensen ◽  
Alicia Lundby ◽  
Shana Claeys ◽  
...  
Keyword(s):  
Cell Survival ◽  
Kinase Inhibitors ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Adaptor Protein ◽  
Therapy Resistance ◽  
Oncogenic Signaling ◽  
Downstream Target ◽  
Anaplastic Lymphoma ◽  
Signaling Axis

Oncogenic anaplastic lymphoma kinase (ALK) is one of the few druggable targets in neuroblastoma, and therapy resistance to ALK-targeting tyrosine kinase inhibitors (TKIs) comprises an inevitable clinical challenge. Therefore, a better understanding of the oncogenic signaling network rewiring driven by ALK is necessary to improve and guide future therapies. Here, we performed quantitative mass spectrometry–based proteomics on neuroblastoma cells treated with one of three clinically relevant ALK TKIs (crizotinib, LDK378, or lorlatinib) or an experimentally used ALK TKI (TAE684) to unravel aberrant ALK signaling pathways. Our integrated proximal proteomics (IPP) strategy included multiple signaling layers, such as the ALK interactome, phosphotyrosine interactome, phosphoproteome, and proteome. We identified the signaling adaptor protein IRS2 (insulin receptor substrate 2) as a major ALK target and an ALK TKI–sensitive signaling node in neuroblastoma cells driven by oncogenic ALK. TKI treatment decreased the recruitment of IRS2 to ALK and reduced the tyrosine phosphorylation of IRS2. Furthermore, siRNA-mediated depletion of ALK or IRS2 decreased the phosphorylation of the survival-promoting kinase Akt and of a downstream target, the transcription factor FoxO3, and reduced the viability of three ALK-driven neuroblastoma cell lines. Collectively, our IPP analysis provides insight into the proximal architecture of oncogenic ALK signaling by revealing IRS2 as an adaptor protein that links ALK to neuroblastoma cell survival through the Akt-FoxO3 signaling axis.

scholarly journals Transcriptome-wide Identification and Characterization of microRNAs and Their Targets in a Highly Adaptable Conifer Platycladus orientalis

2022 ◽  
Vol 147 (1) ◽  
pp. 7-17
Author(s):  
Ying Yang ◽  
Xian-Ge Hu ◽  
Bingsong Zheng ◽  
Yue Li ◽  
Tongli Wang ◽  
...  
Keyword(s):  
Stress Tolerance ◽  
Leucine Zipper ◽  
Class Iii ◽  
Conifer Species ◽  
Essential Information ◽  
Sequencing Platform ◽  
Platycladus Orientalis ◽  
Wide Range ◽  
Identification And Characterization

MicroRNAs (miRNAs) are short noncoding RNAs (20–25 nucleotides) that regulate gene expression posttranscriptionally. However, identification and characterization of miRNAs remain limited for conifer species. In this study, we applied transcriptome-wide miRNAs sequencing to a conifer species Platycladus orientalis, which is highly adaptable to a wide range of environmental adversities, including drought, barren soil, and mild salinity. A total of 17,181,542 raw reads were obtained from the Illumina sequencing platform; 31 conserved and 91 novel miRNAs were identified, and their unique characteristics were further analyzed. Ten randomly selected miRNAs were validated by quantificational real-time polymerase chain reaction. Through miRNA target predictions based on psRNATarget, 2331 unique mRNAs were predicted to be targets of P. orientalis miRNAs that involved in 187 metabolic pathways in KEGG database. These targets included not only important transcription factors (e.g., class III homeodomain leucine zipper targeted by por-miR166d) but also indispensable nontranscriptional factor proteins (i.e., por-miR482a-3p regulated nucleotide-binding site leucine-rich repeat protein). Interestingly, six miRNAs (por-miR16, -miR44, -miR60-5p, -miR69–3p, -miR166b-5p, and -miR395c) were found in adaptation-related pathways (e.g., drought), indicating their possible involved in this species’ stress-tolerance characteristics. The present study provided essential information for understanding the regulatory role of miRNAs in P. orientalis and sheds light on their possible use in tree improvement for stress tolerance.

scholarly journals NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner

2019 ◽  
Vol 11 (11) ◽  
pp. 994-1005 ◽  
Author(s):  
Ran Wei ◽  
Xuguang Liu ◽  
Courtney Voss ◽  
Wentao Qin ◽  
Lina Dagnino ◽  
...  
Keyword(s):  
Cell Fate ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Degradation Pathway ◽  
Anaplastic Lymphoma ◽  
Mechanistic Insight ◽  
Evolutionarily Conserved ◽  
Specific Manner ◽  
Insight Into

Abstract NUMB is an evolutionarily conserved protein that plays an important role in cell adhesion, migration, polarity, and cell fate determination. It has also been shown to play a role in the pathogenesis of certain cancers, although it remains controversial whether NUMB functions as an oncoprotein or tumor suppressor. Here, we show that NUMB binds to anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase aberrantly activated in several forms of cancer, and this interaction regulates the endocytosis and activity of ALK. Intriguingly, the function of the NUMB–ALK interaction is isoform-dependent. While both p66-NUMB and p72-NUMB isoforms are capable of mediating the endocytosis of ALK, the former directs ALK to the lysosomal degradation pathway, thus decreasing the overall ALK level and the downstream MAP kinase signal. In contrast, the p72-NUMB isoform promotes ALK recycling back to the plasma membrane, thereby maintaining the kinase in its active state. Our work sheds light on the controversial role of different isoforms of NUMB in tumorigenesis and provides mechanistic insight into ALK regulation.

scholarly journals SRC Kinase in Glioblastoma: News from an Old Acquaintance

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1558 ◽  
Author(s):  
Claudia Cirotti ◽  
Claudia Contadini ◽  
Daniela Barilà
Keyword(s):  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Metabolic Reprogramming ◽  
Constitutive Activity ◽  
Therapeutic Approaches ◽  
Resistance To Therapy ◽  
Downstream Signaling ◽  
Wide Range ◽  
Therapy Effectiveness

Glioblastoma multiforme (GBM) is one of the most recalcitrant brain tumors characterized by a tumor microenvironment (TME) that strongly supports GBM growth, aggressiveness, invasiveness, and resistance to therapy. Importantly, a common feature of GBM is the aberrant activation of receptor tyrosine kinases (RTKs) and of their downstream signaling cascade, including the non-receptor tyrosine kinase SRC. SRC is a central downstream intermediate of many RTKs, which triggers the phosphorylation of many substrates, therefore, promoting the regulation of a wide range of different pathways involved in cell survival, adhesion, proliferation, motility, and angiogenesis. In addition to the aforementioned pathways, SRC constitutive activity promotes and sustains inflammation and metabolic reprogramming concurring with TME development, therefore, actively sustaining tumor growth. Here, we aim to provide an updated picture of the molecular pathways that link SRC to these events in GBM. In addition, SRC targeting strategies are discussed in order to highlight strengths and weaknesses of SRC inhibitors in GBM management, focusing our attention on their potentialities in combination with conventional therapeutic approaches (i.e., temozolomide) to ameliorate therapy effectiveness.

scholarly journals Meta-analysis of transcriptomic responses to biotic and abiotic stress in tomato

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4631 ◽  
Author(s):  
Elham Ashrafi-Dehkordi ◽  
Abbas Alemzadeh ◽  
Nobukazu Tanaka ◽  
Hooman Razi
Keyword(s):  
Regulatory Networks ◽  
Leucine Zipper ◽  
Expression Profiles ◽  
Meta Analysis ◽  
Ethylene Response Factor ◽  
Plant Tolerance ◽  
Biotic And Abiotic Stress ◽  
Basic Leucine Zipper ◽  
Biotic Stresses ◽  
Wide Range

A wide range of biotic stresses (BS) and abiotic stresses (AS) adversely affect plant growth and productivity worldwide. The study of individual genes cannot be considered as an effective approach for the understanding of tolerance mechanisms, since these stresses are frequent and often in combination with each other, and a large number of genes are involved in these mechanisms. The availability of high-throughput genomic data has enabled the discovery of the role of transcription factors (TFs) in regulatory networks. A meta-analysis of BS and AS responses was performed by analyzing a total of 391 microarray samples from 23 different experiments and 2,336 differentially expressed genes (DEGs) involved in multiple stresses were identified. We identified 1,862 genes differentially regulated in response to BS was much greater than that regulated by AS, 835 genes, and found 15.4% or 361 DEGs with the conserved expression between AS and BS. The greatest percent of genes related to the cellular process (>76% genes), metabolic process (>76% genes) and response to stimulus (>50%). About 4.2% of genes involved in BS and AS responses belonged to the TF families. We identified several genes, which encode TFs that play an important role in AS and BS responses. These proteins included Jasmonate Ethylene Response Factor 1 (JERF1), SlGRAS6, MYB48, SlERF4, EIL2, protein LATE ELONGATED HYPOCOTYL (LHY), SlERF1, WRKY 26, basic leucine zipper TF, inducer of CBF expression 1-like, pti6, EIL3 and WRKY 11. Six of these proteins, JERF1, MYB48, protein LHY, EIL3, EIL2 and SlGRAS6, play central roles in these mechanisms. This research promoted a new approach to clarify the expression profiles of various genes under different conditions in plants, detected common genes from differentially regulated in response to these conditions and introduced them as candidate genes for improving plant tolerance through genetic engineering approach.

scholarly journals Glucocorticoid-Induced Leucine Zipper (GILZ) Over-Expression in T Lymphocytes Inhibits Inflammation and Tissue Damage in Spinal Cord Injury

2011 ◽  
Vol 9 (1) ◽  
pp. 210-225 ◽  
Author(s):  
Emanuela Esposito ◽  
Stefano Bruscoli ◽  
Emanuela Mazzon ◽  
Irene Paterniti ◽  
Maddalena Coppo ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
T Lymphocytes ◽  
Tissue Damage ◽  
Leucine Zipper ◽  
Over Expression ◽  
Cord Injury

scholarly journals Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase.

1993 ◽  
Vol 13 (11) ◽  
pp. 6711-6722 ◽  
Author(s):  
G A Rodrigues ◽  
M Park
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Leucine Zipper ◽  
Kinase Domain ◽  
Site Directed Mutagenesis ◽  
Leucine Zipper Motif ◽  
Transforming Activity ◽  
Met Oncogene ◽  
Hepatocyte Growth

Oncogenic activation of the met (hepatocyte growth factor/scatter factor) receptor tyrosine kinase involves a genomic rearrangement that generates a hybrid protein containing tpr-encoded sequences at its amino terminus fused directly to the met-encoded receptor kinase domain. Deletion of Tpr sequences abolishes the transforming ability of this protein, implicating this region in oncogenic activation. We demonstrate, by site-directed mutagenesis and coimmunoprecipitation experiments, that a leucine zipper motif within Tpr mediates dimerization of the tpr-met product and is essential for the transforming activity of the met oncogene. By analogy with ligand-stimulated activation of receptor tyrosine kinases, we propose that constitutive dimerization mediated by a leucine zipper motif within Tpr is responsible for oncogenic activation of the Met kinase. The possibility that this mechanism of activation represents a paradigm for a class of receptor tyrosine kinase oncogenes activated by DNA rearrangement is discussed.

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