Critical but Distinct Roles for the Pleckstrin Homology and Cysteine-Rich Domains as Positive Modulators of Vav2 Signaling and Transformation
| Autor: | Sharon L. Campbell, Michelle A. Booden, Channing J. Der |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
VAV3
VAV2 RHOA Molecular Sequence Data GTPase GTP Phosphohydrolases Mice Phosphatidylinositol 3-Kinases Transformation Genetic Protein structure Animals Guanine Nucleotide Exchange Factors Humans Point Mutation Amino Acid Sequence Proto-Oncogene Proteins c-vav Cell Growth and Development Molecular Biology Sequence Deletion Oncogene Proteins Sequence Homology Amino Acid biology 3T3 Cells Blood Proteins Cell Biology Phosphoproteins Protein Structure Tertiary Enzyme Activation Pleckstrin homology domain Biochemistry biology.protein Guanine nucleotide exchange factor Signal Transduction |
| Zdroj: | Molecular and Cellular Biology. 22:2487-2497 |
| ISSN: | 1098-5549 |
| Popis: | Vav2, like all Dbl family proteins, possesses tandem Dbl homology (DH) and pleckstrin homology (PH) domains and functions as a guanine nucleotide exchange factor for Rho family GTPases. Whereas the PH domain is a critical positive regulator of DH domain function for a majority of Dbl family proteins, the PH domains of the related Vav and Vav3 proteins are dispensable for DH domain activity. Instead, Vav proteins contain a cysteine-rich domain (CRD) critical for DH domain function. We evaluated the contribution of the PH domain and the CRD to Vav2 guanine nucleotide exchange, signaling, and transforming activity. Unexpectedly, we found that mutations of the PH domain impaired Vav2 signaling, transforming activity, and membrane association. However, these mutations do not influence exchange activity on Rac and only slightly affect exchange on RhoA and Cdc42. We also found that the CRD was critical for the exchange activity in vitro and contributed to Vav2 membrane localization. Finally, we found that phosphoinositol 3-kinase activation synergistically enhanced Vav2 transforming and signaling activity by stimulating exchange activity but not membrane association. In conclusion, the PH domain and CRD are mechanistically distinct, positive modulators of Vav2 DH domain function in vivo. |
| Databáze: | OpenAIRE |
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