An anti-Ras cancer potential of PP1, an inhibitor specific for Src family kinases: in vitro and in vivo studies.

An anti-Ras cancer potential of PP1, an inhibitor specific for Src family kinases: in vitro and in vivo studies. Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

An anti-Ras cancer potential of PP1, an inhibitor specific for Src family kinases: in vitro and in vivo studies. Abstract Text:

G E Gallick,

BACKGROUND: We previously found that both PAK, a Rac/CDC42-activated Ser/Thr kinase, and its binding partner PIX are required for malignant transformation caused by oncogenic Ras mutants, such as v-Ha-Ras. Furthermore, oncogenic Ras requires an autocrine pathway to activate PAK. This pathway involves at least two distinct receptor kinases: EGF receptor (ErbB1) and ErbB2. Interestingly, both of these kinases are known to activate Src family kinases that phosphorylate CAT, another binding partner of PIX. PURPOSE: The major aim of this study was to determine whether Src family kinases are required for both Ras-induced PAK activation and malignant transformation. For this purpose, we used PP1, an inhibitor specific for Src family kinases, which does not inhibit either EGF receptor or ErbB2. METHODS AND RESULTS: We studied the effect of PP1 on the anchorage-dependent growth of normal and v-Ha-Ras transformed NIH 3T3 fibroblasts, PAK activation and anchorage-independent growth of Ras transformants, and development of Ras-induced sarcomas in nude mice. We found that PP1 (10 nM) strongly inhibits PAK activity in Ras transformants. PP1 at this concentration is known to inhibit c-Fyn kinase, but not c-Src kinase, and none of the three known Src family kinases (c-Src, c-Fyn, and c-Yes) expressed in fibroblasts is activated by v-Ha-Ras. Thus, it is most likely that the primary target of this drug is an as yet unidentified Ras-activated Tyr (Y) kinase or kinases, which we call "Ray." Although PP1 has no effect on their anchorage-dependent growth, it significantly inhibits their anchorage-independent growth in soft agar, as well as a rapid growth of Ras-induced sarcomas in mice. CONCLUSION: Like EGF receptor and ErbB2, a member of Src family kinases (most likely a new Src-related kinase called "Ray") is essential for the Ras-induced activation of PAK and the malignant transformation both in vitro and in vivo. These findings suggest that PP1 and other inhibitors specific for Src family kinases are potentially useful for the treatment of Ras-associated cancers.

An anti-Ras cancer potential of PP1, an inhibitor specific for Src family kinases: in vitro and in vivo studies. Publishing Authors By Initials

GE Gallick,

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: 2000 Jul-Aug

An anti-Ras cancer potential of PP1, an inhibitor specific for Src family kinases: in vitro and in vivo studies. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Cancer journal (Sudbury, Mass.)

VOLUME: 6

Page Numbers: 243-8

Journal Abbreviation:

ISSN: 1528-9117

DAY: 19

MONTH: 11

YEAR: 2007

An anti-Ras cancer potential of PP1, an inhibitor specific for Src family kinases: in vitro and in vivo studies. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 100931981

An anti-Ras cancer potential of PP1, an inhibitor specific for Src family kinases: in vitro and in vivo studies. Keywords Mesh Terms:

KEYWORDS: src-Family Kinases

MESH TERMS: physiology

Chemical & Substance for Abstract: An anti-Ras cancer potential of PP1, an inhibitor specific for Src family kinases: in vitro and in vivo studies. Information

Substance Name: Oncogene Protein p21(ras)

Registry Number: EC 3.6.5.2

Grant and Affiliation Information for An anti-Ras cancer potential of PP1, an inhibitor specific for Src family kinases: in vitro and in vivo studies.

AFFILIATION: Ludwig Institute for Cancer Research, Melbourne, Australia.

Country: UNITED STATES

AGENCY:

GRANT:

ACRONYM:

MEDLINETA: Cancer J

REFSOURCE: Cancer J. 2000 Jul-Aug;6(4):217-9

DATABASENAME:

ACCESSION NUMBER:

Number Hits: 0

An anti-Ras cancer potential of PP1, an inhibitor specific for Src family kinases: in vitro and in vivo studies Related Publications

• An anti-Ras cancer potential of PP1, an inhibitor specific for Src family kinases: in vitro and in vivo studies.
• Analysis of the conformational change of myosin during ATP hydrolysis using fluorescence resonance energy transfer.
• Atypical depression as a premonitory symptom of migraine managed by an oral contraceptive.
• Chirped nonlinear pulse propagation in a dispersion-compensated system.
• Conformational change of the loop L5 in rice kinesin motor domain induced by nucleotide binding.
• Depression associated with chronic pain: incidence, characteristics, and long-term outcome.
• Effect of abdominal surgery on glucose tolerance, plasma levels of insulin and glycogenic amino acids.
• Formation and characterization of kinesin.ADP.fluorometal complexes.
• Incorporation of an azobenzene derivative into the energy transducing site of skeletal muscle myosin results in photo-induced conformational changes.
• Intermolecular cross-linking of a novel rice Kinesin k16 motor domain with a photoreactive ATP derivative.
• Optimal design of dispersion management for a soliton wavelength-division-multiplexed system.
• PAK is essential for RAS-induced upregulation of cyclin D1 during the G1 to S transition.
• Photocontrol of Kinesin ATPase activity using an azobenzene derivative.
• Preparation and characterization of a novel rice plant-specific kinesin.
• 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 of breast cancers by the HDAC inhibitor FK228 that blocks the activation of PAK1 and abrogates the tamoxifen-resistance.
• The K252a derivatives, inhibitors for the PAK/MLK kinase family selectively block the growth of RAS transformants.
• The Tyr-kinase inhibitor AG879, that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1 activation and malignant transformation.