Studies on the function of a protein-tyrosine kinase CAKβ/PYK2 and a protein Hic-5 binding to CAKβ

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We have been studying a non-receptor protein-tyrosine kinase of the focal adhesion kinase (FAK) family CAKβ/PYK2. Although CAKβ has been shown to participate in the signal transduction regulating cell movement and cell adhesion, CAKβ is known to localize in the cytoplasm in addition to the focal adhesion. When we expressed a P859A mutant CAKβ in cultured cells, the mutant CAKβ exclusively localized in the cell nucleus, which markedly contrasts to the localization of the wild-type CAKβ. This point mutation disrupts one of the two PXXP motifs in CAKβ important as ligands for the SH3 domain. We obtained evidence indicating that the wild-type CAKβ also shuttles between the cytoplasm and the nucleus. It remains unknown the function of CAKβ in the nucleus. In order to know more about the signaling pathways where CAKβ participates, we tried to find new CAKβ-binding proteins by a screening in the yeast two-hybrid system. One CAKβ-binding protein thus identified was a protein with SUMO ligase E3 activity against transcription factors and others. When this protein was exogenously expressed in H1299 cells, the amount of intracellular p53 significantly increased and the transcription of a p53 reporter was also enhanced. Co-expression of CAKβ with this newly identified protein in H1299 cells resulted in a decrease in the amount of p53 in the cells and also resulted in a suppression of the transcription activity by p53. These results indicate that CAKβ has some function in the nucleus and suggest a functional difference of CAKβ and FAK. It has already been shown that Hic-5, a CAKβ binding protein, functions as a coactivator enhancing the transcriptional activity of the androgen receptor.