Abstract
The focal adhesion kinase (FAK) and cell adhesion kinase beta (CAKbeta, PYK2, CADTK, RAFTK) are highly homologous FAK family members, yet clearly have unique roles in the cell. Comparative analyses of FAK and CAKbeta have revealed intriguing differences in their activities. These differences were investigated further through the characterization of a set of FAK/CAKbeta chimeric kinases. CAKbeta exhibited greater catalytic activity than FAK in vitro, providing a molecular basis for differential substrate phosphorylation by FAK and CAKbeta in vivo. Furthermore, the N terminus may regulate catalytic activity since chimeras containing the FAK N terminus and CAKbeta catalytic domain exhibited a striking high level of catalytic activity and substrate phosphorylation. Unexpectedly, a modulatory role for the N termini in subcellular localization was also revealed. Chimeras containing the FAK N terminus and CAKbeta C terminus localized to focal adhesions, whereas chimeras containing the N and C termini of CAKbeta did not. Finally, prominent changes in cell morphology were induced upon expression of chimeras containing the CAKbeta N terminus, which were not associated with apoptotic cell death, cell cycle progression delay, or changes in Rho activity. These results demonstrate novel regulatory roles for the N terminus of FAK family kinases.
Highlights
Focal adhesion kinase (FAK)1 and cell adhesion kinase  (CAK, known as PYK2, CADTK, or RAFTK) constitute the focal adhesion kinase (FAK) family of cytoplasmic tyrosine kinases
FAK is expressed in most tissues and cell types, and in a wide variety of adherent cells FAK is discretely localized to focal adhesions [5, 6]
A chimeric protein consisting of the N terminus and catalytic domain of CAK fused to the C terminus of FAK was driven to focal adhesions and was strongly regulated by adhesion to fibronectin [14]
Summary
Focal adhesion kinase (FAK) and cell adhesion kinase  (CAK, known as PYK2, CADTK, or RAFTK) constitute the FAK family of cytoplasmic tyrosine kinases. Focal adhesion targeting of FAK is mediated by conserved sequences within the C terminus, designated the Focal Adhesion Targeting (FAT) sequence [18], which shares extensive homology with the C terminus of CAK. Since full-length CAK exhibits focal adhesion localization in only a subset of cells, a functional FAT sequence in the C terminus of CAK appears to be masked in some cell types. This suggests that focal adhesion localization may be regulated on multiple levels. The positive correlation between focal adhesion localization and activation by integrin-mediated adhesion has been reported in the literature and highlights a potential mechanism for differential regulation of FAK and CAK activity [27, 28]
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