Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation.

Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation. Research Abstract Details 

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Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation. Abstract Text:

BACKGROUND: Both EGF family ligands and ErbB family receptor kinases act upstream of RAS to induce mitogenesis of normal cells, such as NIH 3T3 fibroblasts. However, oncogenically mutated RAS, such as v-Ha-RAS is constitutively activated and therefore no longer requires these ligands or receptors for its activation. Nevertheless, it up-regulates the expression of these EGF family ligands. To understand the biologic significance of RAS-induced up-regulation of these ligands in both RAS-induced PAK activation and malignant transformation, we have conducted the following studies, based on the previous observations that (1) the N-terminal SH3 domain of PIX selectively binds a Pro-rich domain of 18 amino acids of PAKs, CDC42/Rac-dependent Ser/Thr kinase family, and (2) this specific interaction is essential for both PAK activation and membrane ruffling RESULTS: Using four distinct, cell-permeable, and highly specific inhibitors, namely WR-PAK18, which blocks the PAK-PIX interaction; AG 1478, which inhibits ErbB1 kinase activity; and AG 825 or AG 879, which inhibits ErbB2 kinase activity, we demonstrate that (1) the PAK-PIX interaction is essential for v-Ha-RAS-induced malignant transformation; (2) v-Ha-RAS requires not only ErbB1 but also ErbB2, which are activated through two independent autocrine pathways to induce both the PIX/Rac/CDC42-dependent PAK activation and malignant transformation in vitro; and (3) a combination of AG 879 and the Src family kinase-specific inhibitor PP1 suppresses almost completely the growth of RAS-induced sarcomas in nude mice. CONCLUSION: These findings not only change our conventional view on the role of these RAS-inducible ligands and ErbB family receptors (serving as RAS activators) but also suggest a new avenue for the treatment of RAS-associated cancers by a combination of inhibitors specific for ERbB, Src, or PAK family kinases.

Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation. Publishing Authors By Initials

For similar enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-tyrosine kinases: src-family kinases research abstracts see: enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-tyrosine kinases: src-family kinases research

PUBMED ID PMID:

MEDLINE DATE: 2001 May-Jun

Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Cancer journal (Sudbury, Mass.)

VOLUME: 7

Page Numbers: 191-202

Journal Abbreviation:

ISSN: 1528-9117

DAY: 19

MONTH: 11

YEAR: 2007

Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 100931981

Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation. Keywords Mesh Terms:

KEYWORDS: src-Family Kinases

MESH TERMS: therapeutic use

Chemical & Substance for Abstract: Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation. Information

Substance Name: Protein Tyrosine Phosphatases

Registry Number: EC 3.1.3.48

Grant and Affiliation Information for Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation.

AFFILIATION: Ludwig Institute for Cancer Research, P.O. Box 2008, Royal Melbourne Hospital, Parkville/Melbourne, Australia 3050.

Country: United States

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MEDLINETA: Cancer J

REFSOURCE: Cancer J. 2001 May-Jun;7(3):178-80

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