Impaired PTPN13 phosphatase activity in spontaneous or HPV-induced squamous cell carcinomas potentiates oncogene signaling through the MAP kinase pathway.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE

Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-

MAP Kinase Signaling System*; Carcinoma, Squamous Cell/*enzymology ; Papillomavirus Infections/*enzymology ; Protein Tyrosine Phosphatase, Non-Receptor Type 13/*genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 13/*metabolism ; Receptor, ErbB-2/*genetics; Animals ; Butadienes/pharmacology ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/pathology ; Carcinoma, Squamous Cell/virology ; Cell Growth Processes/physiology ; Cell Line, Tumor ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Human papillomavirus 16 ; Humans ; MAP Kinase Kinase Kinases/antagonists & inhibitors ; MAP Kinase Kinase Kinases/metabolism ; Mice ; Mice, Inbred C57BL ; Nitriles/pharmacology ; Oncogene Proteins, Viral ; Papillomavirus Infections/pathology ; Phosphorylation ; Protein Tyrosine Phosphatase, Non-Receptor Type 13/deficiency ; Receptor, ErbB-2/metabolism ; Repressor Proteins

Human papillomaviruses (HPVs) are a causative factor in over 90% of cervical and 25% of head and neck squamous cell carcinomas (HNSCCs). The C terminus of the high-risk HPV 16 E6 oncoprotein physically associates with and degrades a non-receptor protein tyrosine phosphatase (PTPN13), and PTPN13 loss synergizes with H-Ras(V12) or ErbB2 for invasive growth in vivo. Oral keratinocytes that have lost PTPN13 and express H-Ras(V12) or ErbB2 show enhanced Ras/RAF/MEK/Erk signaling. In co-transfection studies, wild-type PTPN13 inhibited Ras/RAF/MEK/Erk signaling in HEK 293 cells that overexpress ErbB2, EGFR or H-Ras(V12), whereas an enzymatically inactive PTPN13 did not. Twenty percent of HPV-negative HNSCCs had PTPN13 phosphatase mutations that did not inhibit Ras/RAF/MEK/Erk signaling. Inhibition of Ras/RAF/MEK/Erk signaling using MEK inhibitor U0126 blocked anchorage-independent growth in cells lacking PTPN13. These findings show that PTPN13 phosphatase activity has a physiologically significant role in regulating MAP kinase signaling.

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R01 DE018386 United States DE NIDCR NIH HHS; R01 DE018386-01A1 United States DE NIDCR NIH HHS; United States HHMI Howard Hughes Medical Institute; 1R01DE018386-01A1 United States DE NIDCR NIH HHS

0 (Butadienes)
0 (E6 protein, Human papillomavirus type 16)
0 (Nitriles)
0 (Oncogene Proteins, Viral)
0 (Repressor Proteins)
0 (U 0126)
EC 2.7.10.1 (Receptor, ErbB-2)
EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
EC 2.7.11.25 (MAP Kinase Kinase Kinases)
EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 13)

Date Created: 20090908 Date Completed: 20091204 Latest Revision: 20220311

20240513

PMC2785129

10.1038/onc.2009.251

19734941