Despite its significance in tumor suppression the molecular
Despite its significance in tumor suppression, the molecular mechanism by which DAPK is regulated and its interplay with other tumor suppressors and oncoproteins have not been completely unraveled. Although primarily regulated by CaM binding (Cohen et al., 1997), DAPK activity can also be modulated by posttranslational modifications. Autophosphorylation at S308 inhibits DAPK catalytic activity (Shohat et al., 2001), and this phosphorylation is downregulated under certain death conditions (Shohat et al., 2001, Llambi et al., 2005). Phosphorylation of DAPK at S735 by ERK enhances its kinase activity (Chen et al., 2005), whereas phosphorylation at S289 by RSK attenuates its proapoptotic function (Anjum et al., 2005). The kinase activity of DAPK is required for all biological effects of DAPK, whereas the death domain regulates its proapoptotic function by interacting with ERK (Chen et al., 2005) and UNC5H2 (Llambi et al., 2005). In glatiramer acetate australia to these two domains, the function of DAPK AR domain has not been well defined. Deletion of AR perturbs DAPK cytoskeletal function and subcellular localization (Bialik et al., 2004), whereas overexpressing a segment of AR (residues 451–498) interferes with the death-inducing function of DAPK (Raveh et al., 2000). Although these findings imply a role of AR-mediated protein-protein interaction in modulating DAPK activity, the interacting partner of DAPK AR has not been identified.
Leukocyte common antigen-related protein (LAR, also known as PTPRF) is a receptor-like PTP (RPTP). Its extracellular region contains several immunoglobulin-like and fibronectin (FN) III-like domains, whereas the intracellular region consists of two phosphatase domains, termed D1 and D2. LAR undergoes proteolytic processing to form two noncovalently linked subunits: the extracelluar E subunit (LAR-E) and the phosphatase domain-containing P subunit (LAR-P) (Serra-Pages et al., 1994). Although genetic studies with LAR-deficient mice reveal a role of LAR in mammary gland development, postinjuring nerve regeneration, and cholinergic fiber innervation (Chagnon et al., 2004), the intracellular signaling and physiological substrates of LAR remain poorly characterized. In epithelial cells, LAR associates with cadherin-catenin complex and dephosphorylates β-catenin, which correlate with its abilities to inhibit cell migration and tumor formation (Muller et al., 1999). In addition, LAR interacts with focal adhesion-associated proteins α-liprin (Serra-Pages et al., 1995) and Trio (Debant et al., 1996), thus implicating a role in adhesion signaling and cytoskeleton remodeling.
Introduction ROCO proteins are characterized by the presence of a ROC (Ras of complex proteins)/GTPase domain and a subsequent COR (C-terminal of ROC) domain . There are four human proteins belonging to the ROCO family: leucine-rich repeat kinase (LRRK) 1 and 2, death-associated protein kinase (DAPK) 1 and malignant fibrous histiocytoma amplified sequence 1 (MASL1) . With respect to the central location of the ROC/COR domains, LRRK1 and LRRK2 have a serine/threonine kinase domain situated in their C-terminal part, while the kinase domain of DAPK1 resides in its N-terminus. Closely related to DAPK1, DAPK2 is much shorter than DAPK1 and although the kinase domain is conserved (80% homology), the ROC/COR domains are missing and it does therefore not belong to the ROCO family . As DAPK2 is regulated by Ca2+ and in addition is involved in autophagy [3,4], this protein will also be briefly discussed in this review. In contrast, MASL1 is the only ROCO family member that does not possess kinase activity  and therefore it will not be further discussed. The proximity in ROCO proteins of two enzymatic domains with different catalytic activities in one single protein provides the unique possibility of a mutual regulation and co-operation in orchestrating cellular signals. That such interactions exist became even more evident by the lately described 3D model of LRRK2 homodimers, showing the complexity of LRRK2 as a signaling molecule [5,6].