4 DAPK also operates upstream of p19ARF and p53 to induce apoptosis.5 In addition to its inhibitor Vandetanib transcriptional regulation, DAPK is a subject of post-translational phosphorylation events that might have pro- or anti-apoptotic effects. A recent study reported that the phosphorylation of DAPK at Ser735 by the mitogen-activated protein kinase (MAPK)/extracellular regulated kinase (ERK)1/2 leads to apoptosis-promoting effects in human fibroblasts.6 Furthermore, DAPK promotes the cytoplasmic retention of ERK, thus inhibiting ERK signaling in the nucleus. In addition, the proto-oncogene ribosomal S6 kinase was reported to antagonize the cell death function of DAPK through phosphorylation at Ser289 after phorbol 12-myristate 13-acetate (PMA) exposure in HEK293E cells.

7 Wan et al8 identified DAPK as a target of both tyrosine kinase Src and leukocyte antigen-related phosphatase, both acting in synergism to inactivate DAPK. They were the first to show that this reversible phosphorylation at Tyr491/492 has a physiological relevance in colon cancer. On the other hand, only a few interaction partners of DAPK that do not influence DAPK activity via phosphorylation have been identified.9,10 The p38 MAPK family is known to mediate many processes associated with cell growth, differentiation, survival, and cell death on different stress stimuli.11 Several studies suggest that p38 MAPK may play a dual role in apoptotic cell death where it acts as an apoptosis inducer,12,13 or protects cells from apoptosis.14,15,16,17,18 In this context, p38 MAPK signaling is dependent on both cell-type and stimulus.

11 Despite the above mentioned efforts in identifying activating and inactivating phosphorylation sites, the endogenous DAPK status has never been investigated. The cytokine-dependent DAPK regulation strongly suggests a role for DAPK-mediated apoptosis in the context of immune cell interaction. In this respect, we discussed a new function of DAPK in apoptosis induction during the interaction between colorectal tumor cells and tumor-associated macrophages,19 where higher DAPK expression in tumor cells was significantly associated with a higher apoptotic cell death rate. To understand the endogenous role of DAPK in tumor cell apoptosis, we simulated the in vivo situation using an in vitro model of colorectal tumor cells exposed to macrophage supernatants. We show that in vitro DAPK induction and apoptosis in tumor cells were due to TNF�� release from the activated macrophages. Moreover, we are the first to address that p-p38 MAPK co-localizes and interacts with DAPK Dacomitinib and triggers DAPK-mediated apoptosis in the HCT116 colorectal tumor cells. The physiological relevance of our findings is shown in human colorectal tumors.