Impaired PTPN13 phosphatase activity in spontaneous or HPV-induced squamous cell carcinomas potentiates oncogene signaling through the MAP kinase pathway.
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.
Hoover
A C
AC
Department of Otolaryngology-Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Strand
G L
GL
Nowicki
P N
PN
Anderson
M E
ME
Vermeer
P D
PD
Klingelhutz
A J
AJ
Bossler
A D
AD
Pottala
J V
JV
Hendriks
W J A J
WJ
Lee
J H
JH
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000821:virology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D052162:Human papillomavirus 16; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000494:pharmacology; D009856:Oncogene Proteins, Viral; D030361:Papillomavirus Infections / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins
D002070:Butadienes; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D009570:Nitriles; D009856:Oncogene Proteins, Viral; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D018719:Erb-b2 Receptor Tyrosine Kinases; D012097:Repressor Proteins; C068651:E6 protein, Human papillomavirus type 16; C113580:U 0126