Underphosphorylated BAD interacts with diverse antiapoptotic Bcl-2 family proteins to regulate apoptosis

Survival factors activate kinases which, in turn, phosphorylate the proapoptotic Bcl-xl/Bcl-2-associated death promoter homolog (BAD) protein at key serine residues. Phosphorylated BAD interacts with 14-3-3 proteins, and overexpression of 14-3-3 attenuates BAD-mediated apoptosis. Although BAD is kno...

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Bibliographic Details
Published in:Apoptosis (London) 2001-10, Vol.6 (5), p.319-330
Main Authors: Bae, J, Hsu, S Y, Leo, C P, Zell, K, Hsueh, A J
Format: Article
Language:English
Subjects:
14-3-3 Proteins
Amino Acid Sequence
Animals
Apoptosis
bcl-Associated Death Protein
Binding Sites
Carrier Proteins - genetics
Carrier Proteins - metabolism
Carrier Proteins - physiology
CHO Cells
Conserved Sequence
Cricetinae
Escherichia coli - genetics
Evolution, Molecular
Humans
Kinases
Molecular Sequence Data
Phosphorylation
Proteins
Proto-Oncogene Proteins c-bcl-2 - metabolism
Sequence Homology, Amino Acid
Transfection
Two-Hybrid System Techniques
Tyrosine 3-Monooxygenase - metabolism
Yeasts
Yeasts - genetics
Zebrafish Proteins
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Summary:Survival factors activate kinases which, in turn, phosphorylate the proapoptotic Bcl-xl/Bcl-2-associated death promoter homolog (BAD) protein at key serine residues. Phosphorylated BAD interacts with 14-3-3 proteins, and overexpression of 14-3-3 attenuates BAD-mediated apoptosis. Although BAD is known to interact with Bcl-2, Bcl-w, and Bcl-xL, the exact relationship between BAD and anti- or proapoptotic Bcl-2 proteins has not been analyzed systematically. Using the yeast two-hybrid protein interaction assay, we found that BAD interacted negligibly with proapoptotic Bcl-2 proteins. Even though wild type BAD only interacted with selected numbers of antiapoptotic proteins, underphosphorylated mutant BAD interacted with all antiapoptotic Bcl-2 proteins tested (Bcl-2, Bcl-w, Bcl-xL, Bfl-1/A1, Mcl-1, Ced-9, and BHRF-1). Using nonphosphorylated recombinant BAD expressed in bacteria, direct interactions between BAD and diverse antiapoptotic Bcl-2 members were also observed. Furthermore, apoptosis induced by BAD was blocked by coexpression with Bcl-2, Bcl-w, and Bfl-1. Comparison of BAD orthologs from zebrafish to human indicated the conservation of a 14-3-3 binding site and the BH3 domain during evolution. Thus, highly conserved BAD interacts with diverse antiapoptotic Bcl-2 members to regulate apoptosis.
ISSN:1360-8185
1573-675X
DOI:10.1023/A:1011319901057