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

A C Hoover; G L Strand; P N Nowicki; M E Anderson; P D Vermeer; A J Klingelhutz; A D Bossler; J V Pottala; W J A J Hendriks; J H Lee

doi:10.1038/onc.2009.251

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

Journal article

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Peer reviewed

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

A C Hoover, G L Strand, P N Nowicki, M E Anderson, P D Vermeer, A J Klingelhutz, A D Bossler, J V Pottala, W J A J Hendriks and J H Lee

Oncogene, Vol.28(45), pp.3960-3970

11/12/2009

DOI: 10.1038/onc.2009.251

PMCID: PMC2785129

PMID: 19734941

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https://www.ncbi.nlm.nih.gov/pmc/articles/2785129View

Open Access

Abstract

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.

Phosphorylation

Nitriles - pharmacology

Receptor, ErbB-2 - genetics

Carcinoma, Squamous Cell - genetics

Carcinoma, Squamous Cell - pathology

Carcinoma, Squamous Cell - virology

Humans

Protein Tyrosine Phosphatase, Non-Receptor Type 13 - metabolism

Repressor Proteins

Receptor, ErbB-2 - metabolism

Cell Growth Processes - physiology

Extracellular Signal-Regulated MAP Kinases - metabolism

MAP Kinase Signaling System

Papillomavirus Infections - pathology

Human papillomavirus 16

Protein Tyrosine Phosphatase, Non-Receptor Type 13 - deficiency

Protein Tyrosine Phosphatase, Non-Receptor Type 13 - genetics

MAP Kinase Kinase Kinases - antagonists & inhibitors

Butadienes - pharmacology

Carcinoma, Squamous Cell - enzymology

Papillomavirus Infections - enzymology

Mice, Inbred C57BL

Oncogene Proteins, Viral

MAP Kinase Kinase Kinases - metabolism

Animals

Cell Line, Tumor

Mice

Details

Title: Subtitle: Impaired PTPN13 phosphatase activity in spontaneous or HPV-induced squamous cell carcinomas potentiates oncogene signaling through the MAP kinase pathway
Creators: A C Hoover - Department of Otolaryngology-Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
G L Strand
P N Nowicki
M E Anderson
P D Vermeer
A J Klingelhutz
A D Bossler
J V Pottala
W J A J Hendriks
J H Lee - Sanford Health
Resource Type: Journal article
Publication Details: Oncogene, Vol.28(45), pp.3960-3970
DOI: 10.1038/onc.2009.251
PMID: 19734941
PMCID: PMC2785129
NLM abbreviation: Oncogene
ISSN: 0950-9232
eISSN: 1476-5594
Publisher: England
Grant note: R01 DE018386 / NIDCR NIH HHS 1R01DE018386-01A1 / NIDCR NIH HHS Howard Hughes Medical Institute R01 DE018386-01A1 / NIDCR NIH HHS
Language: English
Date published: 11/12/2009
Academic Unit: Microbiology and Immunology; Pathology; Radiation Oncology
Record Identifier: 9984001144002771

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