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1.
Nat Commun ; 11(1): 4607, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929081

RESUMO

Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Acrilamidas/farmacologia , Idoso de 80 Anos ou mais , Compostos de Anilina/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Imidazóis/farmacologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Pirazinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Regulação para Cima/efeitos dos fármacos
2.
Nat Commun ; 11(1): 4653, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938923

RESUMO

Cancer cells demand excess nutrients to support their proliferation, but how tumours exploit extracellular amino acids during systemic metabolic perturbations remain incompletely understood. Here, we use a Drosophila model of high-sugar diet (HSD)-enhanced tumourigenesis to uncover a systemic host-tumour metabolic circuit that supports tumour growth. We demonstrate coordinate induction of systemic muscle wasting with tumour-autonomous Yorkie-mediated SLC36-family amino acid transporter expression as a proline-scavenging programme to drive tumourigenesis. We identify Indole-3-propionic acid as an optimal amino acid derivative to rationally target the proline-dependency of tumour growth. Insights from this whole-animal Drosophila model provide a powerful approach towards the identification and therapeutic exploitation of the amino acid vulnerabilities of tumourigenesis in the context of a perturbed systemic metabolic network.


Assuntos
Açúcares da Dieta/efeitos adversos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Neoplasias Experimentais/fisiopatologia , Prolina/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos/metabolismo , Animais , Animais Geneticamente Modificados , Carcinogênese , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Hemolinfa/efeitos dos fármacos , Hemolinfa/metabolismo , Larva , Debilidade Muscular/induzido quimicamente , Debilidade Muscular/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/patologia , Neoplasias Experimentais/etiologia , Proteínas Nucleares/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transativadores/genética , Proteínas ras/genética
3.
Adv Exp Med Biol ; 1272: 17-38, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32845500

RESUMO

The tumor microenvironment plays a determining role in cancer development through a plethora of interactions between the extracellular matrix and tumor cells. Decorin is a prototype member of the SLRP family found in a variety of tissues and is expressed in the stroma of various forms of cancer. Decorin has gained recognition for its essential roles in inflammation, fibrotic disorders, and cancer, and due to its antitumor properties, it has been proposed to act as a "guardian from the matrix." Initially identified as a natural inhibitor of transforming growth factor-ß, soluble decorin is emerging as a pan-RTK inhibitor targeting a multitude of RTKs, including EGFR, Met, IGF-IR, VEGFR2, and PDGFR. Besides initiating signaling, decorin/RTK interaction can induce caveosomal internalization and receptor degradation. Decorin also triggers cell cycle arrest and apoptosis and evokes antimetastatic and antiangiogenic processes. In addition, as a novel regulatory mechanism, decorin was shown to induce conserved catabolic processes, such as endothelial cell autophagy and tumor cell mitophagy. Therefore, decorin is a promising candidate for combatting cancer, especially the cancer types heavily dependent on RTK signaling.


Assuntos
Decorina , Neoplasias/metabolismo , Microambiente Tumoral , Autofagia , Decorina/metabolismo , Humanos , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais
4.
Cell ; 182(3): 685-712.e19, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32645325

RESUMO

The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Pneumonia Viral/metabolismo , Proteômica/métodos , Células A549 , Animais , Antivirais/farmacologia , Células CACO-2 , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/metabolismo , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Fosforilação , Pneumonia Viral/virologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
Nat Commun ; 11(1): 3586, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681075

RESUMO

Aberrant expression of receptor tyrosine kinase AXL is linked to metastasis. AXL can be activated by its ligand GAS6 or by other kinases, but the signaling pathways conferring its metastatic activity are unknown. Here, we define the AXL-regulated phosphoproteome in breast cancer cells. We reveal that AXL stimulates the phosphorylation of a network of focal adhesion (FA) proteins, culminating in faster FA disassembly. Mechanistically, AXL phosphorylates NEDD9, leading to its binding to CRKII which in turn associates with and orchestrates the phosphorylation of the pseudo-kinase PEAK1. We find that PEAK1 is in complex with the tyrosine kinase CSK to mediate the phosphorylation of PAXILLIN. Uncoupling of PEAK1 from AXL signaling decreases metastasis in vivo, but not tumor growth. Our results uncover a contribution of AXL signaling to FA dynamics, reveal a long sought-after mechanism underlying AXL metastatic activity, and identify PEAK1 as a therapeutic target in AXL positive tumors.


Assuntos
Movimento Celular , Adesões Focais/metabolismo , Neoplasias/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular Tumoral , Adesões Focais/genética , Humanos , Invasividade Neoplásica , Neoplasias/genética , Neoplasias/fisiopatologia , Paxilina/genética , Paxilina/metabolismo , Fosforilação , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais
6.
Mol Cell ; 79(3): 390-405.e7, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32619402

RESUMO

Despite their apparent lack of catalytic activity, pseudokinases are essential signaling molecules. Here, we describe the structural and dynamic properties of pseudokinase domains from the Wnt-binding receptor tyrosine kinases (PTK7, ROR1, ROR2, and RYK), which play important roles in development. We determined structures of all pseudokinase domains in this family and found that they share a conserved inactive conformation in their activation loop that resembles the autoinhibited insulin receptor kinase (IRK). They also have inaccessible ATP-binding pockets, occluded by aromatic residues that mimic a cofactor-bound state. Structural comparisons revealed significant domain plasticity and alternative interactions that substitute for absent conserved motifs. The pseudokinases also showed dynamic properties that were strikingly similar to those of IRK. Despite the inaccessible ATP site, screening identified ATP-competitive type-II inhibitors for ROR1. Our results set the stage for an emerging therapeutic modality of "conformational disruptors" to inhibit or modulate non-catalytic functions of pseudokinases deregulated in disease.


Assuntos
Moléculas de Adesão Celular/química , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/química , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/química , Sequência de Aminoácidos , Animais , Baculoviridae/genética , Baculoviridae/metabolismo , Sítios de Ligação , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Clonagem Molecular , Cristalografia por Raios X , Expressão Gênica , Humanos , Camundongos , Modelos Moleculares , Células Precursoras de Linfócitos B/citologia , Células Precursoras de Linfócitos B/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Inibidores de Proteínas Quinases/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/antagonistas & inibidores , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Receptores da Família Eph/antagonistas & inibidores , Receptores da Família Eph/química , Receptores da Família Eph/genética , Receptores da Família Eph/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Células Sf9 , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Spodoptera , Homologia Estrutural de Proteína , Especificidade por Substrato
8.
Anticancer Res ; 40(6): 3485-3489, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487648

RESUMO

BACKGROUND/AIM: Despite early detection by widespread use of abdominal imaging more than 40% of patients with conventional renal cell carcinoma (RCC) will die due to metastatic disease. Small kinase inhibitors for AXL receptor tyrosine kinase may delay the progression of metastatic cRCC. PATIENTS AND METHODS: We analysed AXL expression by immunohistochemistry on tissue multi arrays of 691 conventional RCC without metastasis at the time of nephrectomy. RESULTS: The Kaplan-Meier survival analysis indicated a poor disease-specific survival rates for patients with tumour showing cytoplasmic AXL staining, whereas expression on the cell membrane is associated with excellent disease outcome. Multivariate Cox regression analysis identified cytoplasmic AXL expression as an independent prognostic factor indicating a five-times higher risk of postoperative tumour progression (RR=5.048; 95% CI=2.391-10.657; p<0.001). CONCLUSION: Detecting cytoplasmic expression of AXL can be used to define a subset of conventional RCC with high risk of progression, thus identifying patients for more aggressive surveillance and adjuvant AXL inhibitor treatment as early as possible.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/cirurgia , Citoplasma/metabolismo , Progressão da Doença , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Recidiva , Resultado do Tratamento , Adulto Jovem
9.
Nat Commun ; 11(1): 2810, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32499572

RESUMO

The overexpression of the protein tyrosine kinase, Focal adhesion kinase (FAK), in endothelial cells has implicated its requirement in angiogenesis and tumour growth, but how pericyte FAK regulates tumour angiogenesis is unknown. We show that pericyte FAK regulates tumour growth and angiogenesis in multiple mouse models of melanoma, lung carcinoma and pancreatic B-cell insulinoma and provide evidence that loss of pericyte FAK enhances Gas6-stimulated phosphorylation of the receptor tyrosine kinase, Axl with an upregulation of Cyr61, driving enhanced tumour growth. We further show that pericyte derived Cyr61 instructs tumour cells to elevate expression of the proangiogenic/protumourigenic transmembrane receptor Tissue Factor. Finally, in human melanoma we show that when 50% or more tumour blood vessels are pericyte-FAK negative, melanoma patients are stratified into those with increased tumour size, enhanced blood vessel density and metastasis. Overall our data uncover a previously unknown mechanism of tumour growth by pericytes that is controlled by pericyte FAK.


Assuntos
Proteína Rica em Cisteína 61/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neovascularização Patológica , Pericitos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Aorta Torácica/patologia , Carcinoma Pulmonar de Lewis/metabolismo , Adesão Celular , Proliferação de Células , Feminino , Quinase 1 de Adesão Focal/genética , Humanos , Linfocinas/metabolismo , Masculino , Melanoma/irrigação sanguínea , Melanoma/metabolismo , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/patologia , Fator de Crescimento Placentário/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Transdução de Sinais , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
Adv Cancer Res ; 147: 319-373, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32593405

RESUMO

Non-communicable diseases contribute to 71% of the deaths worldwide, of which cancers rank second after cardiovascular diseases. Among all the cancers, head and neck cancers (HNC) are consequential in augmenting the global cancer incidence as well as mortality. Receptor tyrosine kinases (RTKs) are emphatic for the matter that they serve as biomarkers aiding the analysis of tumor progression and metastasis as well as diagnosis, prognosis and therapeutic progression in the patients. The extensive researches on HNC have made significant furtherance in numerous targeted therapies, but for the escalating therapeutic resistance. This review explicates RTKs in HNC, their signaling pathways involved in tumorigenesis, metastasis and stemness induction, the association of non-coding RNAs with RTKs, an overview of RTK based therapy and associated resistance in HNC, as well as a sneak peek into the HPV positive HNC and its therapy. The review extrapolates the cardinal role of RTKs and RTK based therapy as superior to other existing therapeutic interventions for HNC.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais
11.
Adv Cancer Res ; 147: 59-107, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32593407

RESUMO

Signaling functions of plasma membrane-localized receptor tyrosine kinases (RTKs) have been extensively studied after they were first described in the mid-1980s. Plasma membrane RTKs are activated by extracellular ligands and cellular stress stimuli, and regulate cellular responses by activating the downstream effector proteins to initiate a wide range of signaling cascades in the cells. However, increasing evidence indicates that RTKs can also be transported into the intracellular compartments where they phosphorylate traditional effector proteins and non-canonical substrate proteins. In general, internalization that retains the RTK's transmembrane domain begins with endocytosis, and endosomal RTK remains active before being recycled or degraded. Further RTK retrograde transport from endosome-Golgi-ER to the nucleus is primarily dependent on membranes vesicles and relies on the interaction with the COP-I vesicle complex, Sec61 translocon complex, and importin. Internalized RTKs have non-canonical substrates that include transcriptional co-factors and DNA damage response proteins, and many nuclear RTKs harbor oncogenic properties and can enhance cancer progression. Indeed, nuclear-localized RTKs have been shown to positively correlate with cancer recurrence, therapeutic resistance, and poor prognosis of cancer patients. Therefore, understanding the functions of nuclear RTKs and the mechanisms of nuclear RTK transport will further improve our knowledge to evaluate the potential of targeting nuclear RTKs or the proteins involved in their transport as new cancer therapeutic strategies.


Assuntos
Núcleo Celular/enzimologia , Neoplasias/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Endocitose , Humanos , Neoplasias/enzimologia , Neoplasias/patologia , Fosforilação , Transporte Proteico , Transdução de Sinais
12.
Science ; 368(6495): 1132-1135, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32499443

RESUMO

The lumicrine system is a postulated signaling system in which testis-derived (upstream) secreted factors enter the male reproductive tract to regulate epididymal (downstream) pathways required for sperm maturation. Until now, no lumicrine factors have been identified. We demonstrate that a testicular germ-cell-secreted epidermal growth factor-like protein, neural epidermal growth factor-like-like 2 (NELL2), specifically binds to an orphan receptor tyrosine kinase, c-ros oncogene 1 (ROS1), and mediates the differentiation of the initial segment (IS) of the caput epididymis. Male mice in which Nell2 had been knocked out were infertile. The IS-specific secreted proteases, ovochymase 2 (OVCH2) and A disintegrin and metallopeptidase 28 (ADAM28), were expressed upon IS maturation, and OVCH2 was required for processing of the sperm surface protein ADAM3, which is required for sperm fertilizing ability. This work identifies a lumicrine system essential for testis-epididymis-spermatozoa (NELL2-ROS1-OVCH2-ADAM3) signaling and male fertility.


Assuntos
Comunicação Celular/fisiologia , Endopeptidases/metabolismo , Epididimo/metabolismo , Fertilidade , Infertilidade Masculina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Espermatozoides/metabolismo , Testículo/metabolismo , Proteínas ADAM/metabolismo , Animais , Comunicação Celular/genética , Endopeptidases/genética , Infertilidade Masculina/genética , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo
13.
Cancer Sci ; 111(9): 3222-3235, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32589311

RESUMO

Receptor tyrosine kinases (RTKs) and Yes-associated protein (YAP) are critical driving factors in tumors. Currently, the regulation of RTKs in the Hippo-YAP pathway has been recognized as an important issue. However, the relationship between AXL, one of the RTKs, and YAP in head and neck squamous cell carcinoma (HNSCC) remains unknown. In this study, the crosstalk between AXL and YAP was thoroughly investigated in vitro and in vivo. We determined that there was a positive correlation between AXL and YAP in the HNSCC tissue samples and the Cancer Genome Atlas (TCGA) dataset, and high co-expression was associated with poor prognosis. Inhibiting YAP decreased AXL expression in HNSCC cells, while YAP overexpression increased AXL. Moreover, ectopic expression of AXL reversed tumor suppressor phenotypes mediated by YAP silencing. This reversal effect was also confirmed in vivo. In addition, AXL overexpression and Gas6, a ligand of AXL, stimulated YAP dephosphorylation, nuclear translocation, and target gene transcription. AXL inhibition decreased YAP dephosphorylation and nuclear translocation. Mechanistically, Gas6 induced a competitive binding to phosphorylated signal transducers and activators of transcription 3 (STAT3) with large tumor suppressor kinase 1 (LATS1) and inhibited the Hippo pathway. This study revealed a novel non-transcriptional effect of STAT3 in Gas6/AXL-induced YAP activity, suggesting that STAT3 acted as a critical "molecular switch" during the mutual promotion between AXL and YAP, which might be a promising therapeutic target in HNSCC.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos , Fenótipo , Fosforilação , Prognóstico , Modelos de Riscos Proporcionais , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade
15.
PLoS Genet ; 16(5): e1008767, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32357156

RESUMO

Despite the importance of dendritic targeting in neural circuit assembly, the mechanisms by which it is controlled still remain incompletely understood. We previously showed that in the developing Drosophila antennal lobe, the Wnt5 protein forms a gradient that directs the ~45˚ rotation of a cluster of projection neuron (PN) dendrites, including the adjacent DA1 and VA1d dendrites. We report here that the Van Gogh (Vang) transmembrane planar cell polarity (PCP) protein is required for the rotation of the DA1/VA1d dendritic pair. Cell type-specific rescue and mosaic analyses showed that Vang functions in the olfactory receptor neurons (ORNs), suggesting a codependence of ORN axonal and PN dendritic targeting. Loss of Vang suppressed the repulsion of the VA1d dendrites by Wnt5, indicating that Wnt5 signals through Vang to direct the rotation of the DA1 and VA1d glomeruli. We observed that the Derailed (Drl)/Ryk atypical receptor tyrosine kinase is also required for the rotation of the DA1/VA1d dendritic pair. Antibody staining showed that Drl/Ryk is much more highly expressed by the DA1 dendrites than the adjacent VA1d dendrites. Mosaic and epistatic analyses showed that Drl/Ryk specifically functions in the DA1 dendrites in which it antagonizes the Wnt5-Vang repulsion and mediates the migration of the DA1 glomerulus towards Wnt5. Thus, the nascent DA1 and VA1d glomeruli appear to exhibit Drl/Ryk-dependent biphasic responses to Wnt5. Our work shows that the final patterning of the fly olfactory map is the result of an interplay between ORN axons and PN dendrites, wherein converging pre- and postsynaptic processes contribute key Wnt5 signaling components, allowing Wnt5 to orient the rotation of nascent synapses through a PCP mechanism.


Assuntos
Antenas de Artrópodes/crescimento & desenvolvimento , Dendritos/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/crescimento & desenvolvimento , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Wnt/metabolismo , Animais , Antenas de Artrópodes/metabolismo , Axônios/metabolismo , Padronização Corporal , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Membrana/genética , Neurônios Receptores Olfatórios/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais , Proteínas Wnt/genética
16.
Nat Commun ; 11(1): 2291, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385243

RESUMO

PIK3R2 encodes the p85ß regulatory subunit of phosphatidylinositol 3-kinase and is frequently amplified in cancers. The signaling mechanism and therapeutic implication of p85ß are poorly understood. Here we report that p85ß upregulates the protein level of the receptor tyrosine kinase AXL to induce oncogenic signaling in ovarian cancer. p85ß activates p110 activity and AKT-independent PDK1/SGK3 signaling to promote tumorigenic phenotypes, which are all abolished upon inhibition of AXL. At the molecular level, p85ß alters the phosphorylation of TRIM2 (an E3 ligase) and optineurin (an autophagy receptor), which mediate the selective regulation of AXL by p85ß, thereby disrupting the autophagic degradation of the AXL protein. Therapeutically, p85ß expression renders ovarian cancer cells vulnerable to inhibitors of AXL, p110, or PDK1. Conversely, p85ß-depleted cells are less sensitive to these inhibitors. Together, our findings provide a rationale for pharmacological blockade of the AXL signaling axis in PIK3R2-amplified ovarian cancer.


Assuntos
Autofagia , Carcinogênese/metabolismo , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Proteólise , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Intervalo Livre de Doença , Ativação Enzimática , Feminino , Ontologia Genética , Humanos , Lisossomos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas Nucleares , Neoplasias Ovarianas/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ubiquitinação , Regulação para Cima/genética
17.
Cancer Sci ; 111(6): 2052-2061, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32291856

RESUMO

KRAS mutation is frequently seen in a subtype of ovarian cancer categorized as type 1. The KRAS-MAPK pathway, which is closely involved in type 1 cancer progression, is under the regulation of receptor tyrosine kinases (RTKs). AXL, one of the RTKs, has been reported to be overexpressed in ovarian cancer and contributes to the poor prognosis. However, there is no useful target-based agent against such gene profiles. We examined the combined effect of the dual RAF/MEK inhibitor CH5126766 and AXL inhibitor R428 on the growth of ovarian cancer HEY-T30 and OVCAR-5 cell lines, both of which bear KRAS mutation and express AXL at a high level, using the WST-8 assay and the colony formation assay. The synergistic effect of the combination was evaluated by the combination index. The apoptotic cells were analyzed by flow cytometry. The expression of apoptotic proteins and the phosphorylation of MAPK and AKT pathway proteins were investigated by western blotting. We found that CH5126766 and R428 suppressed the phosphorylation of ERK and AKT, respectively, and their combination synergistically inhibited the growth of both cell lines with enhancement of apoptosis accompanied by the Bim upregulation. Combined treatment with CH5126766 and R428 is expected as the novel therapeutic option for KRAS-mutated ovarian cancer with high expression of AXL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzocicloeptenos/farmacologia , Carcinoma Epitelial do Ovário/patologia , Cumarínicos/farmacologia , Triazóis/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores Proteína Tirosina Quinases/metabolismo
18.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188360, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32234337

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with poor prognosis and high mortality. Molecular aberrations associated with PDAC pathogenesis and progression have been extensively investigated. Nevertheless, these findings have not been translated into clinical practice. Lack of therapeutics for PDAC treatment is another challenge. Recent application of molecularly targeted and immunoregulatory therapies appears to be disappointing. Thus, discovery of new targets and therapeutics is urgently needed to combat this malignant disease. The RON receptor tyrosine kinase is a tumorigenic determinant in PDAC malignancy, which provides the rationale to target RON for PDAC treatment. In this review, we summarize the latest evidence of RON in PDAC pathogenesis and the development of anti-RON antibody-drug conjugates for potential PDAC therapy. The finding that anti-RON antibody-drug conjugates show efficacy in preclinical animal models highlights the potential of this novel class of anti-cancer biotherapeutics in future clinical trials.


Assuntos
Anticorpos Monoclonais/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Imunoconjugados/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Anticorpos Monoclonais/uso terapêutico , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Humanos , Imunoconjugados/uso terapêutico , Terapia de Alvo Molecular/métodos , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Nature ; 580(7802): 263-268, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32269334

RESUMO

In cells, organs and whole organisms, nutrient sensing is key to maintaining homeostasis and adapting to a fluctuating environment1. In many animals, nutrient sensors are found within the enteroendocrine cells of the digestive system; however, less is known about nutrient sensing in their cellular siblings, the absorptive enterocytes1. Here we use a genetic screen in Drosophila melanogaster to identify Hodor, an ionotropic receptor in enterocytes that sustains larval development, particularly in nutrient-scarce conditions. Experiments in Xenopus oocytes and flies indicate that Hodor is a pH-sensitive, zinc-gated chloride channel that mediates a previously unrecognized dietary preference for zinc. Hodor controls systemic growth from a subset of enterocytes-interstitial cells-by promoting food intake and insulin/IGF signalling. Although Hodor sustains gut luminal acidity and restrains microbial loads, its effect on systemic growth results from the modulation of Tor signalling and lysosomal homeostasis within interstitial cells. Hodor-like genes are insect-specific, and may represent targets for the control of disease vectors. Indeed, CRISPR-Cas9 genome editing revealed that the single hodor orthologue in Anopheles gambiae is an essential gene. Our findings highlight the need to consider the instructive contributions of metals-and, more generally, micronutrients-to energy homeostasis.


Assuntos
Canais de Cloreto/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Ingestão de Alimentos/fisiologia , Intestinos/fisiologia , Zinco/metabolismo , Animais , Drosophila melanogaster/genética , Enterócitos/metabolismo , Feminino , Preferências Alimentares , Homeostase , Insetos Vetores , Insulina/metabolismo , Ativação do Canal Iônico , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Lisossomos/metabolismo , Masculino , Oócitos/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais , Xenopus
20.
Curr Opin Cell Biol ; 63: 174-185, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32114309

RESUMO

Receptor tyrosine kinases (RTKs) are single-span transmembrane receptors in which relatively conserved intracellular kinase domains are coupled to divergent extracellular modules. The extracellular domains initiate receptor signaling upon binding to either soluble or membrane-embedded ligands. The diversity of extracellular domain structures allows for coupling of many unique signaling inputs to intracellular tyrosine phosphorylation. The combinatorial power of this receptor system is further increased by the fact that multiple ligands can typically interact with the same receptor. Such ligands often act as biased agonists and initiate distinct signaling responses via activation of the same receptor. Mechanisms behind such biased agonism are largely unknown for RTKs, especially at the level of receptor-ligand complex structure. Using recent progress in understanding the structures of active RTK signaling units, we discuss selected mechanisms by which ligands couple receptor activation to distinct signaling outputs.


Assuntos
Ligantes , Receptores Proteína Tirosina Quinases/agonistas , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Ativação Enzimática/efeitos dos fármacos , Humanos , Fosforilação , Receptores Proteína Tirosina Quinases/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
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