Jing Ming, Bohl Joanna, Brimer Nicole, Kinter Michael, Vande Pol Scott B
Department of Pathology, University of Virginia, P.O. Box 800904, Charlottesville, VA 22908, USA.
J Virol. 2007 Mar;81(5):2231-9. doi: 10.1128/JVI.01979-06. Epub 2006 Dec 13.
Oncoproteins from DNA tumor viruses associate with critical cellular proteins to regulate cell proliferation, survival, and differentiation. Human papillomavirus (HPV) E6 oncoproteins have been previously shown to associate with a cellular HECT domain ubiquitin ligase termed E6AP (UBE3A). Here we show that the E6-E6AP complex associates with and targets the degradation of the protein tyrosine phosphatase PTPN3 (PTPH1) in vitro and in living cells. PTPN3 is a membrane-associated tyrosine phosphatase with FERM, PDZ, and PTP domains previously implicated in regulating tyrosine phosphorylation of growth factor receptors and p97 VCP (valosin-containing protein, termed Cdc48 in Saccharomyces cerevisiae) and is mutated in a subset of colon cancers. Degradation of PTPN3 by E6 requires E6AP, the proteasome, and an interaction between the carboxy terminus of E6 and the PDZ domain of PTPN3. In transduced keratinocytes, E6 confers reduced growth factor requirements, a function that requires the PDZ ligand of E6 and that can in part be replicated by inhibiting the expression of PTPN3. This report demonstrates the potential of E6 to regulate phosphotyrosine metabolism through the targeted degradation of a tyrosine phosphatase.
DNA肿瘤病毒的癌蛋白与关键细胞蛋白结合，以调节细胞增殖、存活和分化。人乳头瘤病毒（HPV）E6癌蛋白此前已被证明与一种名为E6AP（UBE3A）的细胞HECT结构域泛素连接酶结合。在此我们表明，E6 - E6AP复合物在体外和活细胞中与蛋白酪氨酸磷酸酶PTPN3（PTPH1）结合并靶向降解它。PTPN3是一种与膜相关的酪氨酸磷酸酶，具有FERM、PDZ和PTP结构域，此前参与调节生长因子受体的酪氨酸磷酸化以及p97 VCP（含缬酪肽蛋白，在酿酒酵母中称为Cdc48），并且在一部分结肠癌中发生突变。E6介导的PTPN3降解需要E6AP、蛋白酶体以及E6羧基末端与PTPN3的PDZ结构域之间的相互作用。在转导的角质形成细胞中，E6降低了对生长因子的需求，这一功能需要E6的PDZ配体，并且部分可通过抑制PTPN3的表达来复制。本报告证明了E6通过靶向降解酪氨酸磷酸酶来调节磷酸酪氨酸代谢的潜力。
