p21-Activated kinases are required for transformation in a cell-based model of neurofibromatosis type 2.
BACKGROUND
NF2 is an autosomal dominant disease characterized by development of bilateral vestibular schwannomas and other benign tumors in central nervous system. Loss of the NF2 gene product, Merlin, leads to aberrant Schwann cell proliferation, motility, and survival, but the mechanisms by which this tumor suppressor functions remain unclear. One well-defined target of Merlin is the group I family of p21-activated kinases, which are allosterically inhibited by Merlin and which, when activated, stimulate cell cycle progression, motility, and increased survival. Here, we examine the effect of Pak inhibition on cells with diminished Merlin function.


RESULTS
Using a specific peptide inhibitor of group I Paks, we show that loss of Pak activity restores normal cell movement in cells lacking Merlin function. In addition, xenografts of such cells form fewer and smaller tumors than do cells without Pak inhibition. However, in tumors, loss of Pak activity does not reduce Erk or Akt activity, two signaling proteins that are thought to mediate Pak function in growth factor pathways.


CONCLUSIONS
These results suggest that Pak functions in novel signaling pathways in NF2, and may serve as a useful therapeutic target in this disease.
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
Hoi Yee
HY
Chow
Dina
D
Stepanova
Jennifer
J
Koch
Jonathan
J
Chernoff
D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D048430:Cell Shape; D002471:Cell Transformation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016518:Neurofibromatosis 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
D025581:Neurofibromin 2; D054462:p21-Activated Kinases