DAP-kinase is a pro-apoptotic Ca(2+)
calmodulin-regulated
serine/threonine kinase that participates in a wide array of apoptotic systems initiated by
interferon-gamma,
TNF-alpha, activated Fas, and detachment from extracellular matrix. It was isolated by an unbiased functional approach to gene cloning aimed at hitting central mediators of the apoptotic process. This 160 Kd
protein kinase is localized to actin microfilaments and carries interesting modules such as ankyrin repeats and the death domain. The death promoting effects of
DAP-kinase depend on its intact catalytic activity, the correct intracellular localization, and on the presence of the death domain. A few mechanisms restrain the killing effects of the
protein in healthy cells. The
enzyme's active site is negatively controlled by an adjacent CaM regulatory domain whose effect is relieved by binding to Ca(2+)-activated
calmodulin. A second mode of autoinhibition engages the
serine-rich C-terminal tail, spanning the last 17
amino acids of the
protein. A link between
DAP-kinase and
cancer has been established. It was found that the
mRNA and
protein expression is frequently lost in various human
cancer cell lines. Analysis of the methylation status of
DAP-kinase's
5' UTR in
DNA extracted from fresh
tumor samples, showed high incidence of hypermethylation in several human
carcinomas and B cell
malignancies. The anti-tumorigenic effect of
DAP-kinase was also studied experimentally in mouse model systems where the re-introduction of
DAP-kinase into highly metastatic mouse lung
carcinoma cells who had lost the
protein, strongly reduced their metastatic capacity. Thus, it appears that loss of
DAP-kinase confers a selective advantage to
cancer cells and may play a causative role in
tumor progression. A few novel
kinases sharing high homology in their catalytic domains with
DAP-kinase have been recently identified constituting altogether a novel family of death promoting
serine/threonine kinases.