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J. Biol. Chem., Vol. 278, Issue 20, 18671-18681, May 16, 2003

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Specific ₁ Integrin Site Selectively Regulates Akt/Protein Kinase B Signaling via Local Activation of Protein Phosphatase 2A^*

Roumen Pankov^§, Edna Cukierman^¶, Katherine Clark, Kazue Matsumoto, Cornelia Hahn, Benoit Poulin, and Kenneth M. Yamada

From the  Craniofacial Developmental Biology and Regeneration Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892-4370 and the  Laboratory of Cell Signaling, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-0320

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 ₁ 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  integrin cytoplasmic domains, we identified the tryptophan residue at position 775 of human ₁ integrin as specific and necessary for integrin-mediated protein kinase B/Akt survival signaling. Stable expression of a ₁ integrin mutated at this amino acid in GD25 ₁-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 ₁ 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 ₁ integrin-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.

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