A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor.
BACKGROUND
Neurofibromatosis type 2 is a group of tumors caused by loss-of-function mutations of a tumor suppressor gene encoding NF2/merlin. Development of chemotherapeutics for this disease, which often threatens the life of young children, has been hampered by a limited information on the signaling function of NF2. NF2 can inhibit Ras-induced malignant transformation. However, the primary (signaling) target of NF2 in the oncogenic pathway has not been previously identified.


RESULTS
Here, using a series of NF2 constructs, we show that NF2 inhibits directly the Rac/CDC42-dependent Ser/Thr kinase PAK1, which is essential for both Ras transformation and neurofibromatosis type 1 (NF1), through two separate domains. A mutant of NF2, that lacks the PAK1-inhibiting domain of 78 amino acids (NF78C, residues 447-524), fails to suppress Ras transformation. Furthermore, PAK1-specific inhibitors CEP-1347 and WR-PAK18 selectively inhibit the growth of NF2-deficient cancer cells, but not NF2-positive cells.


CONCLUSIONS
These results suggest that PAK1 is essential for the malignant growth of NF2-deficient cells, and that PAK1-blocking drugs could be potentially useful forthe treatment of neurofibromatosis types 2, in addition to Ras-induced cancers and neurofibromatosis type 1.
Ludwig Institute for Cancer Research, Melbourne, Australia.
Yumiko
Y
Hirokawa
Anjali
A
Tikoo
John
J
Huynh
Tamara
T
Utermark
C Oliver
CO
Hanemann
Marco
M
Giovannini
Guang-Hui
GH
Xiao
Joseph R
JR
Testa
John
J
Wood
Hiroshi
H
Maruta
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D016515:Genes, Neurofibromatosis 2 / Q000502:physiology*; D011905:Genes, ras / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016518:Neurofibromatosis 2 / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D025581:Neurofibromin 2 / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D054462:p21-Activated Kinases
D025581:Neurofibromin 2; C515903:PAK1 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases