RESUMEN
Fungi infection, especially derived from Plasmopara viticola, causes severe grapevine economic losses worldwide. Despite the availability of chemical treatments, looking for eco-friendly ways to control Vitis vinifera infection is gaining much more attention. When a plant is infected, multiple disease-control molecular mechanisms are activated. PRRs (Pattern Recognition Receptors) and particularly RLKs (receptor-like kinases) take part in the first barrier of the immune system, and, as a consequence, the kinase signaling cascade is activated, resulting in an immune response. In this context, discovering new lectin-RLK (LecRLK) membrane-bounded proteins has emerged as a promising strategy. The genome-wide localization of potential LecRLKs involved in disease defense was reported in two grapevine varieties of great economic impact: Chardonnay and Pinot Noir. A total of 23 potential amino acid sequences were identified, exhibiting high-sequence homology and evolution related to tandem events. Based on the domain architecture, a carbohydrate specificity ligand assay was conducted with docking, revealing two sequences as candidates for specific Vitis vinifera-Plasmopara viticola host-pathogen interaction. This study confers a starting point for designing new effective antifungal treatments directed at LecRLK targets in Vitis vinifera.
Asunto(s)
Oomicetos , Filogenia , Enfermedades de las Plantas , Proteínas de Plantas , Vitis , Vitis/genética , Vitis/microbiología , Vitis/metabolismo , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Receptores de Reconocimiento de Patrones/metabolismo , Receptores de Reconocimiento de Patrones/genética , Receptores de Reconocimiento de Patrones/química , Interacciones Huésped-Patógeno/genética , Secuencia de Aminoácidos , Simulación del Acoplamiento Molecular , Simulación por ComputadorRESUMEN
3-Poly-phosphoinositides (PIP3) regulate cell survival, division, and migration. Both PI3-kinase (phosphoinositide-3-kinase) and PTEN (phosphatase and tensin-homolog in chromosome 10) control PIP3 levels, but the mechanisms connecting PI3-kinase and PTEN are unknown. Using non-transformed cells, the activation kinetics of PTEN and of the PIP3-effector AKT were examined after the addition of growth factors. Both epidermal growth factor and serum induced the early activation of AKT and the simultaneous inactivation of PTEN (at ~5 min). This PIP3/AKT peak was followed by a general reduction in AKT activity coincident with the recovery of PTEN phosphatase activity (at ~10-15 min). Subsequent AKT peaks and troughs followed. The fluctuation in AKT activity was linked to that of PTEN; PTEN reconstitution in PTEN-null cells restored AKT fluctuations, while PTEN depletion in control cells abrogated them. The analysis of PTEN activity fluctuations after the addition of growth factors showed its inactivation at ~5 min to be simultaneous with its transient ubiquitination, which was regulated by the ubiquitin E3 ligase cCBL (casitas B-lineage lymphoma proto-oncogene). Protein-protein interaction analysis revealed cCBL to be brought into the proximity of PTEN in a PI3-kinase-dependent manner. These results reveal a mechanism for PI3-kinase/PTEN crosstalk and suggest that cCBL could be new target in strategies designed to modulate PTEN activity in cancer.
Asunto(s)
Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-cbl/metabolismo , Animales , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Factor de Crecimiento Epidérmico/farmacología , Receptores ErbB/metabolismo , Células HEK293 , Humanos , Ratones , Células 3T3 NIH , Fosfatos de Fosfatidilinositol/metabolismo , Fosforilación/efectos de los fármacos , Factor de Crecimiento Derivado de Plaquetas/farmacología , Suero/metabolismo , Ubiquitinación/efectos de los fármacosRESUMEN
Despite interest in phosphoinositide (PtdIns) kinases, such as PtdIns 3 kinases (PI3K), as targets for controlling plasma membrane PtdIns levels in disease, the PtdIns have another less well-known site of action in the cell nucleus.Recent studies show that PtdIns use a variety of strategies to alter DNA responses. Here, we provide an overview of these newly identified forms of gene expression control, which should be considered when studying the therapeutic use of PtdIns-directed compounds. As PI3K is one of the most important clinical targets in recent years, we will focus on two polyphosphoinositides, the PI3K substrate PtdIns(4,5)di-phosphate (PI4,5P2) and its product PtdIns(3,4,5)tri-phosphate (PI3,4,5P3).
Asunto(s)
Membrana Celular/química , Núcleo Celular/química , Fosfatos de Fosfatidilinositol/fisiología , Fosfatidilinositoles/fisiología , Humanos , Fosfatidilinositol 3-QuinasasRESUMEN
Dysregulation of the PI3K/PTEN pathway is a frequent event in cancer, and PIK3CA and PTEN are the most commonly mutated genes after TP53. PIK3R1 is the predominant regulatory isoform of PI3K. PIK3R2 is an ubiquitous isoform that has been so far overlooked, but data from The Cancer Genome Atlas shows that increased expression of PIK3R2 is also frequent in cancer. In contrast to PIK3R1, which is a tumor-suppressor gene, PIK3R2 is an oncogene. We review here the opposing roles of PIK3R1 and PIK3R2 in cancer, the regulatory mechanisms that control PIK3R2 expression, and emerging therapeutic approaches targeting PIK3R2.
Asunto(s)
Biomarcadores de Tumor , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Susceptibilidad a Enfermedades , Neoplasias/etiología , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Animales , Adhesión Celular , Fosfatidilinositol 3-Quinasa Clase Ia/química , Fosfatidilinositol 3-Quinasa Clase Ia/genética , Humanos , Neoplasias/patología , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/genética , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Transporte de Proteínas , Transducción de Señal , Relación Estructura-Actividad , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Oncogenic mutations in the PI3K/AKT pathway are present in nearly half of human tumors. Nonetheless, inhibitory compounds of the pathway often induce pathway rebound and tumor resistance. We find that lung squamous cell carcinoma (SQCC), which accounts for ~20% of lung cancer, exhibits increased expression of the PI3K subunit PIK3R2, which is at low expression levels in normal tissues. We tested a new approach to interfere with PI3K/AKT pathway activation in lung SQCC. We generated tumor xenografts of SQCC cell lines and examined the consequences of targeting PIK3R2 expression. In tumors with high PIK3R2 expression, and independently of PIK3CA, KRAS, or PTEN mutations, PIK3R2 depletion induced lung SQCC xenograft regression without triggering PI3K/AKT pathway rebound. These results validate the use PIK3R2 interfering tools for the treatment of lung squamous cell carcinoma.