Degradation of tyrosine phosphatase PTPN3 (PTPH1) by association with oncogenic human papillomavirus E6 proteins.
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.
Jing
Ming
M
Department of Pathology, University of Virginia, P.O. Box 800904, Charlottesville, VA 22908, USA.
Bohl
Joanna
J
Brimer
Nicole
N
Kinter
Michael
M
Vande Pol
Scott B
SB
D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000235:genetics; D052162:Human papillomavirus 16 / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D054589:Protein Tyrosine Phosphatase, Non-Receptor Type 3; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
C068651:E6 protein, Human papillomavirus type 16; D008024:Ligands; D046912:Multiprotein Complexes; D009856:Oncogene Proteins, Viral; D011994:Recombinant Proteins; D012097:Repressor Proteins; D004247:DNA; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; C516656:PTPN3 protein, human; D054589:Protein Tyrosine Phosphatase, Non-Receptor Type 3; D017027:Protein Tyrosine Phosphatases