Regulation of Focal Adhesion Kinase by Its Amino-Terminal Domain through an Autoinhibitory Interaction

AUTOR(ES)

Cooper, Lee Ann

FONTE

American Society for Microbiology

RESUMO

We have investigated a role for the amino-terminal FERM-like domain of the focal adhesion kinase (FAK) as a negative regulator of its own activity and phosphorylation state. Deletion of the first 375 amino acids from the amino terminus of FAK increases its catalytic activity in vitro, its phosphorylation when expressed in mammalian cells, and the phosphorylation of a FAK substrate, paxillin. Deletion mutants are phosphorylated in suspension, suggesting that they are no longer regulated by adhesion. The amino terminus of FAK can interact with the kinase domain of FAK in vitro and in vivo, suggesting that it might act as an autoinhibitor of FAK activity. The amino terminus of FAK can act in trans to inhibit FAK phosphorylation when expressed in mammalian cells or to directly inhibit FAK activity in vitro. Expression of the amino terminus of FAK inhibits cell cycle progression in CHO cells, consistent with its inhibition of FAK phosphorylation and function in trans. A glutathione S-transferase fusion protein containing the cytoplasmic tail of the β1 integrin stimulates FAK activity in vitro, suggesting that FAK could be regulated by molecular interactions with the amino terminus. Based on these and previous data, we propose a working model for activation of FAK in cell adhesion.

Documentos Relacionados

• Constitutive activation of S6 kinase by deletion of amino-terminal autoinhibitory and rapamycin sensitivity domains.
• Oncogenic transformation by vrel requires an amino-terminal activation domain.
• p59fyn tyrosine kinase associates with multiple T-cell receptor subunits through its unique amino-terminal domain.
• Tiny T antigen: an autonomous polyomavirus T antigen amino-terminal domain.
• Arm-site binding by λ-integrase: Solution structure and functional characterization of its amino-terminal domain