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- Title
A Dual Role of EGFR Protein Tyrosine Kinase Signaling in Ubiquitination of AAV2 Capsids and Viral Second-strand DNA Synthesis.
- Authors
Li Zhong; Weihong Zhao; Jianqing Wu; Baozheng Li; Zolotukhin, Sergei; Govindasamy, Lakshmanan; Agbandje-McKenna, Mavis; Srivastava, Arun
- Abstract
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.Molecular Therapy (2007) 15 7, 1323–1330. doi:10.1038/sj.mt.6300170
- Subjects
EPIDERMAL growth factor; PROTEIN-tyrosine kinases; DNA; GENE therapy; T-cell receptor genes
- Publication
Molecular Therapy, 2007, Vol 15, Issue 7, p1323
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1038/sj.mt.6300170