**1. Introduction: DAPKs, MAPKs**

Death-associated protein kinase (DAPK) family proteins are closely related, Ca2+/calmodulin (CaM)-regulated serine/threonine kinases, whose members not only possess significant homology in their catalytic domains but also share cell death-associated functions [1,2]. DAPK family proteins include DAPK1, DAPK2, DAPK3, and DAPK-related apoptosis-inducing protein kinases (DRAK-1 and DRAK-2) [3–7] (Figure 1). DAPK1 has multiple complex domains including an N-terminal kinase domain, a Ca2+/CaM-binding domain, a series of ankyrin repeats, a cytoskeleton binding domain, and a carboxyl-terminal death domain. DAPK2 contains an N-terminal kinase domain with high homology to DAPK1 catalytic domain [5], a conserved CaM-binding autoregulatory domain, and a C-terminal tail with no homology to any known proteins [6]. DAPK3 has an N-terminal kinase domain, a leucine zipper domain, and two putative nuclear localization sequences (NLS) [8]. The kinase domain and death domain are both critical for its pro-apoptotic activity [1,2,9]. All of these kinases are closely related to each other, sharing about 80% identity in their kinase domains [3,6], except for DRAK-1 and DRAK-2, whose kinase domains are only 50% identical to DAPK1 [10].

Mitogen-activated protein kinases (MAPKs) are an important sub-family of non-receptor serine-threonine kinases. MAPKs mediate signal transduction pathways that are involved in cellular responses to a diverse range of stimuli, such as mitogens, hormones, osmotic stress, heat shock, proinflammatory cytokines, and significant developmental changes in organisms. They mediate cellular functions including proliferation, differentiation, mitosis, gene expression, and apoptosis [11]. Extracellular stimuli such as growth factors result in a sequential phosphorylation cascade that

ultimately leads to activation of MAPKs. Once activated, MAPKs activate downstream signals and transcription factors. MAPKs mainly consist of the extracellular signal-regulated kinases (ERK1–8), p38 MAPKs (p38α–δ), and c-Jun N-terminal kinases (JNK1–3) [12]. While the ERKs are mainly activated in response to proliferative signals, p38s and JNKs are activated in response to various stresses. Although there are several MAPK isoforms, the best-investigated ones are ERK1/2, JNK1/2, and p38α.

The mutual regulation between MAPK and DAPK family proteins plays a role in apoptosis regulation and several diseases. In this review, we introduce the reports showing the regulatory mechanisms and various functions of DAPK family proteins. Furthermore, we refer to reports indicating the relationship between DAPK and MAPK family proteins in multiple diseases.
