PAK kinase regulates Rac GTPase and is a potential target in human schwannomas

被引：34

作者：

Flaiz, Christine ^{[1
]}

Chernoff, Jonathan ^{[2
]}

Ammoun, Sylwia ^{[1
]}

Peterson, Jeffrey R. ^{[2
]}

Hanemann, Clemens O. ^{[1
]}

机构：

[1] Peninsula Coll Med & Dent, Plymouth PL6 8BU, Devon, England

[2] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA

来源：

EXPERIMENTAL NEUROLOGY | 2009年 / 218卷 / 01期

关键词：

Schwannoma; PAK; Merlin; Small GTPases; NF2; TUMOR-SUPPRESSOR; P21-ACTIVATED KINASE; ADHERENS JUNCTIONS; GROWTH-FACTORS; BETA-PIX; CELLS; MERLIN; ACTIVATION; INHIBITOR; ADHESION;

D O I：

10.1016/j.expneurol.2009.04.019

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Merlin loss causes benign tumours of the nervous system, mainly schwannomas and meningiomas. Schwannomas show enhanced Rac1 and Cdc42 activity, the p21-activated kinase 2 (PAK2) activation and increased ruffling and cell adhesion. PAK regulates activation of merlin. PAK has been proposed as a potential therapeutic target in schwannomas. However where PAK stands in the Rac pathway is insufficiently characterised. We used a novel small-molecule PAK inhibitor, IPA-3, to investigate the role of PAK activation on Rac1/Cdc42 activity, cell spreading and adhesion in human primary schwannoma and Schwann cells. We show that IPA-3 blocks activation of PAK2 at Ser192/197 that antagonises PAK's interaction with Pix. Accordingly, Pix-mediated Rac1 activation is decreased in IPA-3 treated schwannoma cells, indicating that PAK acts upstream of Rac. We show that this Rac activation at the level of focal adhesions in schwannoma cells is essential for cell spreading and adhesion in Schwann and schwannoma cells. (C) 2009 Elsevier Inc. All rights reserved.

引用

页码：137 / 144

页数：8

共 33 条

[21] THE SMALL GTP-BINDING PROTEIN RHO REGULATES THE ASSEMBLY OF FOCAL ADHESIONS AND ACTIN STRESS FIBERS IN RESPONSE TO GROWTH-FACTORS [J].

RIDLEY, AJ ;

HALL, A .

CELL, 1992, 70 (03) :389-399

[22]

Rosenbaum JamesE., 1998, Social Pyschology of Education, V2, P55, DOI DOI 10.1023/A:1009653501824

[23] αPIX and βPIX and their role in focal adhesion formation [J].

Rosenberger, G ;

Kutsche, K .

EUROPEAN JOURNAL OF CELL BIOLOGY, 2006, 85 (3-4) :265-274

[24] The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling [J].

Shaw, RJ ;

Paez, JG ;

Curto, M ;

Yaktine, A ;

Pruitt, WM ;

Saotome, I ;

O'Bryan, JP ;

Gupta, V ;

Ratner, N ;

Der, CJ ;

Jacks, T ;

McClatchey, AI .

DEVELOPMENTAL CELL, 2001, 1 (01) :63-72

[25] The lamellipodium: where motility begins [J].

Small, JV ;

Stradal, T ;

Vignal, E ;

Rottner, K .

TRENDS IN CELL BIOLOGY, 2002, 12 (03) :112-120

[26] Targeting and activation of Rac1 are mediated by the exchange factor β-Pix [J].

ten Klooster, JP ;

Jaffer, ZM ;

Chernoff, J ;

Hordijk, PL .

JOURNAL OF CELL BIOLOGY, 2006, 172 (05) :759-769

[27] Neuregulin and laminin stimulate phosphorylation of the NF2 tumor suppressor in Schwann cells by distinct protein kinase A and p21-activated kinase-dependent pathways [J].

Thaxton, C. ;

Lopera, J. ;

Bott, M. ;

Fernandez-Valle, C. .

ONCOGENE, 2008, 27 (19) :2705-2715

[28] Phosphorylation of the NF2 tumor suppressor in Schwann cells is mediated by Cdc42-Pak and requires paxillin binding [J].

Thaxton, Courtney ;

Lopera, Jorge ;

Bott, Marga ;

Baldwin, M. Elizabeth ;

Kalidas, Poonam ;

Fernandez-Valle, Cristina .

MOLECULAR AND CELLULAR NEUROSCIENCE, 2007, 34 (02) :231-242

[29] Rearrangements of the intermediate filament GFAP in primary human schwannoma cells [J].

Utermark, T ;

Schubert, SJA ;

Hanemann, CO .

NEUROBIOLOGY OF DISEASE, 2005, 19 (1-2) :1-9

[30]

Utermark T, 2005, BRAIN PATHOL, V15, P17

← 1 2 3 4 →