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rdf:type |
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lifeskim:mentions |
umls-concept:C0018270,
umls-concept:C0027627,
umls-concept:C0033414,
umls-concept:C0037083,
umls-concept:C0069515,
umls-concept:C0205263,
umls-concept:C0242957,
umls-concept:C0813622,
umls-concept:C0919267,
umls-concept:C1419227,
umls-concept:C1704675,
umls-concept:C1710082
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pubmed:issue |
52
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pubmed:dateCreated |
2001-12-25
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pubmed:abstractText |
In this study we initially examined the interaction between CD44v3 (a hyaluronan (HA) receptor) and Vav2 (a guanine nucleotide exchange factor) in human ovarian tumor cells (SK-OV-3.ipl cell line). Immunological data indicate that both CD44v3 and Vav2 are expressed in SK-OV-3.ipl cells and that these two proteins are physically linked as a complex in vivo. By using recombinant fragments of Vav2 and in vitro binding assays, we have detected a specific binding interaction between the SH3-SH2-SH3 domain of Vav2 and the cytoplasmic domain of CD44. In addition, we have observed that the binding of HA to CD44v3 activates Vav2-mediated Rac1 signaling leading to ovarian tumor cell migration. Further analyses indicate that the adaptor molecule, growth factor receptor-bound protein 2 (Grb2) that is bound to p185(HER2) (an oncogene product), is also associated with the CD44v3-Vav2 complex. HA binding to SK-OV-3.ipl cells promotes recruitment of both Grb2 and p185(HER2) to the CD44v3-Vav2 complex leading to Ras activation and ovarian tumor cell growth. In order to determine the role of Grb2 in CD44v3 signaling, we have transfected SK-OV-3.ipl cells with Grb2 mutant cDNAs (e.g. Delta N-Grb2 that has a deletion in the amino-terminal SH3 domain or Delta C-Grb2 that has a deletion in the carboxyl-terminal SH3 domain). Our results clearly indicate that the SH3 domain deletion mutants of Grb2 (i.e. the Delta N-Grb2 (and to a lesser extent the Delta C-Grb2) mutant) not only block their association with p185(HER2) but also significantly impair their binding to the CD44v3-Vav2 complex and inhibit HA/CD44v3-induced ovarian tumor cell behaviors. Taken together, these findings strongly suggest that the interaction of CD44v3-Vav2 with Grb2-p185(HER2) plays an important role in the co-activation of both Rac1 and Ras signaling that is required for HA-mediated human ovarian tumor progression.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adaptor Proteins, Signal Transducing,
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD44,
http://linkedlifedata.com/resource/pubmed/chemical/CD44V3,8-10,
http://linkedlifedata.com/resource/pubmed/chemical/GRB2 Adaptor Protein,
http://linkedlifedata.com/resource/pubmed/chemical/GRB2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Guanine Nucleotide Exchange Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Guanosine Triphosphate,
http://linkedlifedata.com/resource/pubmed/chemical/Hyaluronic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-vav,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, erbB-2,
http://linkedlifedata.com/resource/pubmed/chemical/VAV2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/rac1 GTP-Binding Protein,
http://linkedlifedata.com/resource/pubmed/chemical/ras GTPase-Activating Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
28
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pubmed:volume |
276
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
48679-92
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:11606575-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:11606575-Animals,
pubmed-meshheading:11606575-Antibodies, Monoclonal,
pubmed-meshheading:11606575-Antigens, CD44,
pubmed-meshheading:11606575-Cell Division,
pubmed-meshheading:11606575-Cell Movement,
pubmed-meshheading:11606575-Female,
pubmed-meshheading:11606575-GRB2 Adaptor Protein,
pubmed-meshheading:11606575-Guanine Nucleotide Exchange Factors,
pubmed-meshheading:11606575-Guanosine Triphosphate,
pubmed-meshheading:11606575-Humans,
pubmed-meshheading:11606575-Hyaluronic Acid,
pubmed-meshheading:11606575-Models, Biological,
pubmed-meshheading:11606575-Oncogene Proteins,
pubmed-meshheading:11606575-Ovarian Neoplasms,
pubmed-meshheading:11606575-Protein Binding,
pubmed-meshheading:11606575-Proteins,
pubmed-meshheading:11606575-Proto-Oncogene Proteins c-vav,
pubmed-meshheading:11606575-Radioligand Assay,
pubmed-meshheading:11606575-Receptor, erbB-2,
pubmed-meshheading:11606575-Signal Transduction,
pubmed-meshheading:11606575-Tumor Cells, Cultured,
pubmed-meshheading:11606575-rac1 GTP-Binding Protein,
pubmed-meshheading:11606575-ras GTPase-Activating Proteins,
pubmed-meshheading:11606575-src Homology Domains
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pubmed:year |
2001
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pubmed:articleTitle |
Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185(HER2) and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth.
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pubmed:affiliation |
Enocrine Unit, Department of Medicine, University of California and Veterans Affairs Medical Center, San Francisco, California 94121, USA. lillyb@itsa.ucsf.edu
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't
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