[HTML][HTML] A dual role of EGFR protein tyrosine kinase signaling in ubiquitination of AAV2 capsids and viral second-strand DNA synthesis
L Zhong, W Zhao, J Wu, B Li, S Zolotukhin… - Molecular Therapy, 2007 - cell.com
L Zhong, W Zhao, J Wu, B Li, S Zolotukhin, L Govindasamy, M Agbandje-McKenna…
Molecular Therapy, 2007•cell.comA 52 kd cellular protein, FK506-binding protein (FKBP52), phosphorylated at tyrosine
residues by epidermal growth factor receptor protein tyrosine kinase (EGFR-PTK), inhibits
adeno-associated virus 2 (AAV2) second-strand DNA synthesis and transgene expression.
FKBP52 is dephosphorylated at tyrosine residues by T-cell protein tyrosine phosphatase
(TC-PTP), and TC-PTP over-expression leads to improved viral second-strand DNA
synthesis and improved transgene expression. In these studies, we observed that …
residues by epidermal growth factor receptor protein tyrosine kinase (EGFR-PTK), inhibits
adeno-associated virus 2 (AAV2) second-strand DNA synthesis and transgene expression.
FKBP52 is dephosphorylated at tyrosine residues by T-cell protein tyrosine phosphatase
(TC-PTP), and TC-PTP over-expression leads to improved viral second-strand DNA
synthesis and improved transgene expression. In these studies, we observed that …
A 52 kd cellular protein, FK506-binding protein (FKBP52), phosphorylated at tyrosine residues by epidermal growth factor receptor protein tyrosine kinase (EGFR-PTK), inhibits adeno-associated virus 2 (AAV2) second-strand DNA synthesis and transgene expression. FKBP52 is dephosphorylated at tyrosine residues by T-cell protein tyrosine phosphatase (TC-PTP), and TC-PTP over-expression leads to improved viral second-strand DNA synthesis and improved transgene expression. In these studies, we observed that perturbation of EGFR-PTK signaling by a specific inhibitor, Tyrphostin 23 (Tyr23), augmented the transduction efficiency of the single-stranded AAV (ssAAV) vector as well as the self-complementary AAV (scAAV) vector. Similarly, tyrosine-dephosphorylation of FKBP52 by TC-PTP resulted in increased transduction by both vectors. These data suggested that EGFR-PTK signaling also affects aspects of AAV transduction other than viral second-strand DNA synthesis. We document that inhibition of EGFR-PTK signaling leads to decreased ubiquitination of AAV2 capsids which, in turn, facilitates nuclear transport by limiting proteasome-mediated degradation of AAV vectors. We also document that Tyr23-mediated increase in AAV2 transduction efficiency is not further enhanced by a specific proteasome inhibitor, MG132. Thus, EGFR-PTK signaling modulates ubiquitin (Ub)/proteasome pathway-mediated intracellular trafficking as well as FKBP52-mediated second-strand DNA synthesis of AAV2 vectors. This has implications in the optimal use of AAV vectors in gene therapy.
cell.com
以上显示的是最相近的搜索结果。 查看全部搜索结果