Functional analysis of adapter protein c-Abl Src homology 3 domain-binding protein 2.
Notice bibliographique
Résumé
3BP2 is a pleckstrin homology (PH) domain- and Src homology 2 (SH2) domain-containing adapter protein that has been linked through genetic evidence to a rare human disease called cherubism 146. 3BP2 was originally cloned in a screen to identify c-Abl SH3 binding proteins 23,24. In overexpression studies, 3BP2 has been implicated as a positive regulatory adapter molecule coupled to immunoreceptor on T cells 67,69,70, B cells 68, NK cells 71-73 and mast cells 74,75. It was also evident that 3BP2 forms complexes with a number of signaling molecules, such as Zap-70, LAT, phospholipase C-γ1 (PLC-γ1), Grb2, Cbl, and Fyn in Jurkat cells 67 and Vav1, Vav2, PLC-γ, and Syk in Daudi B cells 68. Despite the growing body of biochemical data to support the importance of 3BP2 in cells of the hematopoietic lineage, a clear picture of the biological function of 3BP2 has yet to emerge. To elucidate the in vivo function of 3BP2, our laboratory has generated 3BP2 gene-deficient mice through homologous recombination 452. The 3BP2-deficient (3BP2-/-) mice were born at the expected Mendelian frequency and were fertile and viable. 3BP2-/- mice accumulate splenic marginal-zone (MZ) B cells, possess a reduced frequency of peritoneal B-1 B cells, and have a diminished thymus-independent type 2 (TI-2) antigen response. 3BP2-/- B cells demonstrate diminished proliferation and cell survival following cross-linking of the B-cell receptor (BCR). Following BCR ligation, 3BP2 might be recruited to BCR complex through its inducible interaction with BCR costimulatory molecule CD19. In the absence of 3BP2, the activation of BCR downstream effectors such as MAPK Erk1/2, JNK, and c-Abl is normal; however, 3BP2 deficiency leads to defects in Syk phosphorylation and calcium flux. In addition to defects in peripheral B cell activities, 3BP2 deficiency contributes to defects in neutrophil activities. In response to the chemotactic peptide, fMLF, 3BP2-/- neutrophils fail to establish directional migration in vitro. There is a defect in the accumulation of filamentous actin at the leading edge of migrating 3BP2-/- neutrophils which might be responsible for the random movement of these cells under shallow gradient of fMLF. In vivo, there is a delay in the recruitment of circulating neutrophils to the site of chemically induced inflammation in 3BP2-/- mice. Compared to wildtype neutrophils, 3BP2-/- neutrophils fail to properly produce superoxide anion (O2-) following fMLF stimulation. Defects in both directional migration and superoxide production of 3BP2-/- neutrophils might contribute to the reduction in bacteria clearance and the increased mortality in 3BP2-/- mice post Listeria Monocytogenes infection. In Chapter 1 of this thesis, I have reviewed basic structures and functions of the domain modules found in adapter proteins. In addition, I have reviewed the findings from numerous reports on the function of 3BP2 in different cell types. A discussion of the physical appearance and some of the initial characterization of 3BP2-deficient mice (3BP2-/-) we have generated in our laboratory are included in Chapter 1. The second part of Chapter 1 consists of an introduction on B cell receptor signaling pathway and B-cell development and activation. A discussion of G protein-coupled receptor-mediated neutrophil functions can also be found in Chapter 1. Chapter 2 contains all the methods and materials used in my study. Chapter 3 includes the characterization of peripheral B cell compartment of 3BP2-/- mice as well as the role of 3BP2 downstream of B-cell antigen receptor and in T-independent immune response. In chapter 4, I present data from experiments designed to examine the role of 3BP2 downstream of a G protein-coupled receptor, fMLF receptor, of neutrophils. I also show the requirement of 3BP2 in the clearance of Listeria Monocytogenes. In chapter 5, I propose two models for 3BP2 action based on the findings in B cells and neutrophils and discuss future areas for investigation.
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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 ».