title: MKP-3 regulates PDGF-BB effects and MAPK activation in meningioma cells.
abstract: Autocrine platelet derived growth factor-BB (PDGF-BB) and cerebrospinal fluid, which also contains PDGF, stimulate proliferation of leptomeningeal and meningioma cells, in part, by activation of the Raf-1-MEK-1-MAPK pathway. The negative regulators of this activation are not known. However, PDGF receptors and p44/42 MAPK are regulated, in part, by mitogen activated kinase phosphatase 3 (MKP-3) and Src homology carboxyl terminus protein (SHP-2). Six fetal and one adult human leptomeninges specimens and 22 meningiomas were evaluated for MKP-3, SHP-2, and phospho-SHP-2 as well as activation/phosphorylation of MEK1/2, p44/42 MAPK, Akt and signal transducer and activator of transcription 3 (STAT3) by western blot and MKP3 expression by polymerase chain reaction. PDGF-BB and cerebrospinal fluid effects on these phosphatases and signaling were also studied in vitro. MKP-3 and phospho-p44/42 MAPK were detected in all or six of seven leptomeninges, respectively. MKP-3 was detected in six of eight World Health Organization grade I and II meningiomas. Three of four grade I and five of five grade II with no or low MKP-3 had high levels of phospho-p44/42MAPK. MKP3 was not detected in four of six grade III meningiomas. These had high levels of phospho-p44/42MAPK. SHP2 was found in all leptomeninges and meningiomas while phospho-SHP-2 was found in 11 to 33% of grade I-III meningiomas. Reduced MKP-3 may facilitate PDGF-BB autocrine and paracrine mitogenic effects in a subpopulation of higher grade meningiomas by increasing phospho-p44/42 MAPK.
authors.affiliation: Department of Pathology, Division of Neuropathology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 626, Rochester, NY 14623, USA. Electronic address: mahlon_johnson@urmc.rochester.edu.
authors.forename: Mahlon D
authors.initials: MD
authors.lastname: Johnson
authors.affiliation: Department of Urology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Jay E
authors.initials: JE
authors.lastname: Reeder
authors.affiliation: Department of Pathology, Division of Neuropathology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 626, Rochester, NY 14623, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: O'Connell
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000077214:Becaplermin; D054642:Dual Specificity Phosphatase 6 / Q000378:metabolism*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008577:Meningeal Neoplasms / Q000378:metabolism* / Q000473:pathology; D008578:Meninges / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008579:Meningioma / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D054642:Dual Specificity Phosphatase 6; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: Leptomeninges; MEK 1/2; MKP-3; Meningioma; Phosphatases; SHP2; p44/42 MAPK