Abstract 992: LIMD2 is a small LIM-only protein overexpressed in metastatic lesions which regulates cell motility and tumor progression by directly binding to and activating the integrin-linked-kinase
Notice bibliographique
Résumé
Abstract Proteins that communicate signals from the cytoskeleton to the nucleus are prime targets for effectors of metastasis as they often transduce signals regulating adhesion, motility and invasiveness. LIM domain proteins shuttle between the cytoplasm and the nucleus, and bind to partners in both compartments, often coupling changes in gene expression to extracellular cues and hence are a prime target for deregulation during tumor progression and metastasis. The LIM domain is a modular Zn finger structure, often found tandemly repeated in proteins. These LIM arrays often serve as scaffolds for assembling signal transduction apparatus. In this work, we characterize LIMD2 which is unique in that it encodes a single LIM domain. LIMD2 was originally identified as a transcript overexpressed in metastatic lesions but absent in the matched primary tumor from the same patient suggesting that it may be either a marker or effector of metastatic spread. We have shown that LIMD2 levels in fresh and archival tumors positively correlate with cell motility, metastatic potential and tumor grade in many different tumor types including bladder, melanoma, breast and thyroid tumors. LIMD2 directly contributes to these cellular phenotypes as shown by overexpression, knockdown and reconstitution experiments in cell culture models. Tumor cells with poor metastatic capability are converted to highly motile, invasive cells by expression of LIMD2 suggesting a dominant gain of function action. To understand the molecular mechanisms of its biological effects we determined its solution structure using NMR. The structure studies of LIMD2 revealed a classic LIM-domain structure containing a rigid hydrophobic core which bound 2 molecules of Zn. The 3D structure of LIMD2 was most highly related to the LIM1 domain of PINCH1, a core component of the Integrin Linked Kinase-Parvin-Pinch (IPP) complex. The IPP complex plays a key role in cell-cell and cell matrix interaction by transducing signals from membrane bound integrins to the nucleus. Structural and biochemical analyses revealed that LIMD2 bound directly to the kinase domain of ILK near the active site and strongly activated ILK kinase activity in vitro. Immunolocalization studies showed that LIMD2 and components of the IPP complex co-existed in focal adhesion plaques. Cells which were null for ILK failed to respond to the induction of motility and invasion by ectopic expression of LIMD2. This strongly suggests that LIMD2 potentiates its biological effects through direct interactions with ILK, a signal transduction pathway firmly linked to cell motility and invasion. In summary, we have defined LIMD2 as a new component of the signal transduction cascade that links integrin-mediated signaling to cell motility/metastatic behavior and may be a promising target for controlling tumor spread. Citation Format: Hongzhuang Peng, Mehdi Taleb Zadeh Farrooji, Michael J. Osborne, Jeremy W. Prokop, Paul C. McDonald, Jayashree Karar, Zhaoyuan Hou, Mei He, Electron Kebebew, Torben Orntoft, Meenhard Herlyn, Andrew J. Caton, William Fredericks, Bruce Malkowicz, Christopher S. Paterno, Alexandra S. Carolin, David W. Speicher, Emmanuel Skordalakes, Qihong Huang, Shoukat S. Dedhar, Katherine L. B. Borden, Frank J. Rauscher. LIMD2 is a small LIM-only protein overexpressed in metastatic lesions which regulates cell motility and tumor progression by directly binding to and activating the integrin-linked-kinase. [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 992. doi:10.1158/1538-7445.AM2014-992
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| 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) | 0,002 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».