Specific β1 Integrin Site Selectively Regulates Akt/Protein Kinase B Signaling via Local Activation of Protein Phosphatase 2A*
By R. Pankov, E. Cukierman, K. Clark, Kazue Matsumoto, Cornelia S. Hahn, B. Poulin, Kenneth M. Yamada. Journal of Biological Chemistry, 2003
89 citations recorded by the source corpus.
Integrin transmembrane receptors generate multiple signals, but how they mediate specific signaling is not clear. Here we test the hypothesis that particular sequences along the β1 integrin cytoplasmic domain may exist that are intimately related to specific integrin-mediated signaling pathways. Using systematic alanine mutagenesis of amino acids conserved between different β integrin cytoplasmic domains, we identified the tryptophan residue at position 775 of human β1 integrin as specific and necessary for integrin-mediated protein kinase B/Akt survival signaling. Stable expression of a β1 integrin mutated at this amino acid in GD25 β1-null cells resulted in reduction of Akt phosphorylation at both Ser473 and Thr308 activation sites. As a consequence, the cells were substantially more sensitive to serum starvation-induced apoptosis when compared with cells expressing wild type β1 integrin. This inactivation of Akt resulted from increased dephosphorylation by a localized active population of protein phosphatase 2A. Both Akt and protein phosphatase 2A were present in β1integrin-organized cytoplasmic complexes, but the activity of this phosphatase was 2.5 times higher in the complexes organized by the mutant integrin. The mutation of Trp775 specifically affected Akt signaling, without effects on other integrin-activated pathways including phosphoinositide 3-kinase, MAPK, JNK, and p38 nor did it influence activation of the integrin-responsive kinases focal adhesion kinase and Src. The identification of Trp775 as a specific site for integrin-mediated Akt signaling supports the concept of specificity of signaling along the integrin cytoplasmic domain.
Subfields: Immunology, Immunology and Allergy, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/c8418cd45df08ffe0ea5a9854f82c84b490d30a0
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In Immunology and Allergy
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Citations in the corpus
- Genetic and cell biological analysis of integrin outside-in signaling. (2009, background): “The ability of b1 integrin to directly bind and activate PP2A, which on the other hand is inactivated by mTOR, could provide a mechanism by which integrins locally switch on and off Akt signaling (Peterson et al. 1999; Ivaska et al. 2002; Pankov et al. 2003).”