Abstract 135: Phosphorylation and furin-mediated processing are critical posttranslational modifications of the KISS1 metastasis suppressor
Notice bibliographique
Résumé
Abstract Originally discovered as a metastasis suppressor, KISS1 has since been defined as a neurotransmittor and regulator of diverse cellular functions and has been implicated in pathologies such as hypogonadism and Alzheimer's disease. Several laboratories are actively developing therapies based upon KISS1 biology. KISS1 is secreted and processed into small peptides (called kisspeptins (KP)) in the extracellular milieu. However, the enzyme(s) responsible for generation of KP from nascent KISS1 is unknown, although sequence analysis (cleavage at KR or RR dibasic sites) suggests that proprotein convertases (PC) are responsible. We hypothesized that enzyme(s) belonging to the PC family processes KISS1 to generate KP. KISS1 processing was completely inhibited by treatment with PC inhibitors Dec-RVKR-CMK and a1-PDX in these cells multiple tumor cell lines. Further, mRNA expression of the seven members of the PC family showed consistent expression of only three proteases - furin, PCSK5 and PCSK7 narrowing the candidate proteases. Only shRNA-mediated knockdown of furin (i.e., not PCSK5 or PCSK7) blocked KISS1 processing. Thus furin is the essential enzyme responsible for KP generation. Even when cells were exposed to Dec-RVKR-CMK or shRNA targeting furin, two bands (Mr∼15.9 kDa and Mr ∼17 kDa) were consistently detected in SDS-PAGE of conditioned medium. This observation suggested KISS1 could either be alternatively post-translationally modified or that another protease (family) might also cleave KISS1. To investigate the possibility that KISS1 may be post-translationally modified, potential sites of O-glycosylation (NetOGlyc 4.0) or serine/threonine phosphorylation (NetPhos 2.0) were analyzed in silico. Three amino acid residues (T69, S70, and S72)of the native KISS1 protein showed highest scores as being either O-glycosylated or phosphorylated. Further, mutation of these three residues to alanine resulted in the loss of the higher molecular weight band which was co-localized to a band detected using anti-phospho Ser/Thr strongly suggesting that KISS1 is indeed phosphorylated. This is the first report of phosphorylation of KISS1. Studies are underway to identify the kinase(s) and phosphatase(s) involved as well as the functional significance of the phosphorylation. Support: CA134981, National Foundation for Cancer Research, Steiner Family Fellowship in Metastasis Research, Susan G. Komen for the Cure SAC110037. Citation Format: Sitaram Harihar, Kelsey R. Hampton, Tomoo Iwakuma, Nabil G. Seidah, Danny R. Welch. Phosphorylation and furin-mediated processing are critical posttranslational modifications of the KISS1 metastasis suppressor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 135. doi:10.1158/1538-7445.AM2014-135
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».