A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor.

Abstract

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.

• Authors: Yumiko Hirokawa, Anjali Tikoo, John Huynh, Tamara Utermark, C Oliver Hanemann, Marco Giovannini, Guang-Hui Xiao, Joseph R Testa, John Wood, Hiroshi Maruta
• Journal: Cancer journal (Sudbury, Mass.) (Cancer J) 2004 Jan-Feb Vol. 10 Issue 1 Pg. 20-6 ISSN: 1528-9117 [Print] United States
• PMID: 15000491 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Neurofibromin 2
• PAK1 protein, human
• Protein Serine-Threonine Kinases
• p21-Activated Kinases
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Mitogen-Activated Protein Kinase Kinases

Topics

• Animals
• Cell Transformation, Neoplastic (drug effects, genetics)
• Gene Expression Regulation, Enzymologic (drug effects, physiology)
• Gene Expression Regulation, Neoplastic (drug effects, physiology)
• Genes, Neurofibromatosis 2 (physiology)
• Genes, ras (physiology)
• Humans
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, metabolism)
• Neurofibromatosis 2 (drug therapy, enzymology, genetics)
• Neurofibromin 2 (genetics, pharmacology, physiology, therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, pharmacology, therapeutic use)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Tumor Cells, Cultured
• p21-Activated Kinases