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

Experimental Neurology

Volumn 218, Issue 1, 2009, Pages 137-144

  Flaiz, Christine ^a   Chernoff, Jonathan ^b   Ammoun, Sylwia ^a   Peterson, Jeffrey R ^b   Hanemann, Clemens O ^a  

^a PENINSULA MEDICAL SCHOOL   (United Kingdom)

^b FOX CHASE CANCER CENTER   (United States)

Author keywords

Merlin; PAK; Schwannoma; Small GTPases

Indexed keywords

GUANINE NUCLEOTIDE BINDING PROTEIN; GUANOSINE TRIPHOSPHATASE ACTIVATING PROTEIN; MERLIN; P21 ACTIVATED KINASE 2; PROTEIN CDC42; PROTEIN KINASE INHIBITOR; RAC1 PROTEIN; SERINE;

ARTICLE; CELL ADHESION; CELL SPREADING; CONTROLLED STUDY; DRUG TARGETING; ENZYME ACTIVATION; ENZYME REGULATION; FOCAL ADHESION; HUMAN; HUMAN CELL; NEURILEMOMA; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN DEPLETION; PROTEIN INTERACTION; SCHWANN CELL;

CELL ADHESION; CELL SURVIVAL; CELLS, CULTURED; DISULFIDES; DOSE-RESPONSE RELATIONSHIP, DRUG; ENZYME ACTIVATION; ENZYME INHIBITORS; ENZYME-LINKED IMMUNOSORBENT ASSAY; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; NAPHTHOLS; NEURILEMMOMA; P21-ACTIVATED KINASES; RAC GTP-BINDING PROTEINS; SCHWANN CELLS; SERINE; TIME FACTORS;

EID: 67349256384     PISSN: 00144886     EISSN: 10902430     Source Type: Journal    
DOI: 10.1016/j.expneurol.2009.04.019     Document Type: Article

References (33)

1. Ammoun S., Flaiz C., Ristic N., Schuldt J., and Hanemann C.O. Dissecting and targeting the growth factor-dependent and growth factor-independent extracellular signal-regulated kinase pathway in human schwannoma. Cancer Res. 68 (2008) 5236-5245
2. Beeser A., Jaffer Z.M., Hofmann C., and Chernoff J. Role of group A p21-activated kinases in activation of extracellular-regulated kinase by growth factors. J. Biol. Chem. 280 (2005) 36609-36615
3. Benninger Y., Thurnherr T., Pereira J.A., Krause S., Wu X., Chrostek-Grashoff A., Herzog D., Nave K.A., Franklin R.J., Meijer D., Brakebusch C., Suter U., and Relvas J.B. Essential and distinct roles for cdc42 and rac1 in the regulation of Schwann cell biology during peripheral nervous system development. J. Cell Biol. 177 (2007) 1051-1061
4. Bokoch G.M. Biology of the p21-activated kinases. Annu. Rev. Biochem. 72 (2003) 743-781
5. Calabrese E.J. Hormesis: why it is important to toxicology and toxicologists. Environ. Toxicol. Chem. 27 (2008) 1451-1474
6. Deacon S.W., Beeser A., Fukui J.A., Rennefahrt U.E., Myers C., Chernoff J., and Peterson J.R. An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase. Chem. Biol. 15 (2008) 322-331
7. Flaiz C., Ammoun S., Biebl A., and Hanemann C.O. Altered adhesive structures and their relation to RhoGTPase activation in merlin-deficient Schwannoma. Brain Pathol. 19 (2009) 27-38
8. Flaiz C., Kaempchen K., Matthies C., and Hanemann C.O. Actin-rich protrusions and nonlocalized GTPase activation in Merlin-deficient Schwannomas. J. Neuropathol. Exp. Neurol. 66 (2007) 608-616
9. Flaiz C., Utermark T., Parkinson D.B., Poetsch A., and Hanemann C.O. Impaired intercellular adhesion and immature adherens junctions in merlin-deficient human primary schwannoma cells. GLIA 56 (2008) 506-515
10. Hanemann C.O., Bartelt-Kirbach B., Diebold R., Kampchen K., Langmesser S., and Utermark T. Differential gene expression between human schwannoma and control Schwann cells. Neuropathol. Appl. Neurobiol. 32 (2006) 605-614
11. Hirokawa Y., Tikoo A., Huynh J., Utermark T., Hanemann C.O., Giovannini M., Xiao G.H., Testa J.R., Wood J., and Maruta H. A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor. Cancer J. 10 (2004) 20-26
12. Kaempchen K., Mielke K., Utermark T., Langmesser S., and Hanemann C.O. Upregulation of the Rac1/JNK signaling pathway in primary human schwannoma cells. Hum. Mol. Genet. 12 (2003) 1211-1221
13. Kissil J.L., Wilker E.W., Johnson K.C., Eckman M.S., Yaffe M.B., and Jacks T. Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p21-activated kinase, Pak1. Mol. Cell 12 (2003) 841-849
14. Lallemand D., Curto M., Saotome I., Giovannini M., and McClatchey A.I. NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes Dev. (2003) 1090-1100
15. Manser E., Leung T., Salihuddin H., Zhao Z.S., and Lim L. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature 367 (1994) 40-46
16. Manser E., Loo T.H., Koh C.G., Zhao Z.S., Chen X.Q., Tan L., Tan I., Leung T., and Lim L. PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. Mol. Cell 1 (1998) 183-192
17. Nakai Y., Zheng Y., MacCollin M., and Ratner N. Temporal control of Rac in Schwann cell-axon interaction is disrupted in NF2-mutant schwannoma cells. J. Neurosci. 26 (2006) 3390-3395
18. Nodari A., Zambroni D., Quattrini A., Court F.A., D'Urso A., Recchia A., Tybulewicz V.L., Wrabetz L., and Feltri M.L. Beta1 integrin activates Rac1 in Schwann cells to generate radial lamellae during axonal sorting and myelination. J. Cell Biol. 177 (2007) 1063-1075
19. Obermeier A., Ahmed S., Manser E., Yen S.C., Hall C., and Lim L. PAK promotes morphological changes by acting upstream of Rac. EMBO J. 17 (1998) 4328-4339
20. Pelton P.D., Sherman L.S., Rizvi T.A., Marchionni M.A., Wood P., Friedman R.A., and Ratner N. Ruffling membrane, stress fiber, cell spreading and proliferation abnormalities in human Schwannoma cells. Oncogene 17 (1998) 2195-2209
21. Ridley A.J., and Hall A. The small GTP-binding protein Rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70 (1992) 389-399
22. Rosenbaum C., Kluwe L., Mautner V.F., Friedrich R.E., Mueller H.W., and Hanemann C.O. Isolation and characterization of Schwann cells from neurofibromatosis type 2 patients. Neurobiol. Dis. 5 (1998) 55-64
23. Rosenberger G., and Kutsche K. AlphaPIX and betaPIX and their role in focal adhesion formation. Eur. J. Cell Biol. 85 (2006) 265-274
24. Shaw R.J., Paez J.G., Curto M., Yaktine A., Pruitt W.M., Saotome I., O'Bryan J.P., Gupta V., Ratner N., Der C.J., Jacks T., and McClatchey A.I. The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling. Dev. Cell 1 (2001) 63-72
25. Small J.V., Stradal T., Vignal E., and Rottner K. The lamellipodium: where motility begins. Trends Cell Biol. 12 (2002) 112-120
26. ten Klooster J.P., Jaffer Z.M., Chernoff J., and Hordijk P.L. Targeting and activation of Rac1 are mediated by the exchange factor beta-Pix. J. Cell Biol. 172 (2006) 759-769
27. Thaxton C., Lopera J., Bott M., Baldwin M.E., Kalidas P., and Fernandez-Valle C. Phosphorylation of the NF2 tumor suppressor in Schwann cells is mediated by Cdc42-Pak and requires paxillin binding. Mol. Cell Neurosci. 34 (2007) 231-242
28. Thaxton C., Lopera J., Bott M., and Fernandez-Valle C. Neuregulin and laminin stimulate phosphorylation of the NF2 tumor suppressor in Schwann cells by distinct protein kinase A and p21-activated kinase-dependent pathways. Oncogene 27 (2008) 2705-2715
29. Utermark T., Kaempchen K., and Hanemann C.O. Pathological adhesion of primary human schwannoma cells is dependent on altered expression of integrins. Brain Pathol. 13 (2003) 352-363
30. Utermark T., Kaempchen K., Antoniadis G., and Hanemann C.O. Reduced apoptosis rates in human schwannomas. Brain Pathol. 15 (2005) 17-22
31. Utermark T., Schubert S.J., and Hanemann C.O. Rearrangements of the intermediate filament GFAP in primary human schwannoma cells. Neurobiol. Dis. 19 (2005) 1-9
32. Xiao G.H., Beeser A., Chernoff J., and Testa J.R. p21-activated kinase links Rac/Cdc42 signaling to Merlin. J. Biol. Chem. 277 (2002) 883-886
33. Zhao Z.S., and Manser E. PAK and other Rho-associated kinases-effectors with surprisingly diverse mechanisms of regulation. Biochem. J. 386 (2005) 201-214