The tumor suppressor WARTS activates the Omi / HtrA2-dependent pathway of cell death

Abstract

Drosophila tumor suppressor WARTS (Wts) is an evolutionally conserved serine/threonine kinase and participates in a signaling complex that regulates both proliferation and apoptosis to ensure the proper size and shape of the fly. Human counterparts of this complex have been found to be frequently downregulated or mutated in cancers. WARTS, a human homolog of Wts, is also known as tumor suppressor and mitotic regulator, but its molecular implications in tumorigenesis are still obscure. Here, we show that WARTS binds via its C-terminus to the PDZ domain of a proapoptotic serine protease Omi/ HtrA2. Depletion of WARTS inhibited Omi/HtrA2-mediated cell death, whereas overexpression of WARTS promoted this process. Furthermore, WARTS can enhance the protease activity of Omi/HtrA2 both in vivo and in vitro. Activation of Omi/HtrA2-mediated cell death is thus a potential mechanism for the tumor suppressive activity of WARTS.

Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

“…We found that WTS can promote the protease activity of Omi to induce cell death (Kuninaka et al, 2005). However, recent reports using Omi protease mutant or knockout mice indicate that loss of protein or protease activity of Omi sensitizes some types of cell death stimuli, which contradicts the previous findings.…”

“…Therefore, binding of these two molecules is important for signal transduction. When the C-terminal three amino acids (Val-Tyr-Val) of WTS are removed it is prevented from associating with Omi (Kuninaka et al, 2005). As LATS2 (LTS2), another member of the class of mammalian WTS/ LATS1 kinase, has the same three C-terminal amino acids as WTS, it is possible that LTS2 also contributes to the Omi-mediated signaling pathway.…”

“…Whereas the Wts DN2 (Figure 1c) was cleaved by wt Omi in a time-dependent manner in vitro, but not the DN2-DVYV (which also lacks the three C-terminal amino acids and does not bind to Omi (Kuninaka et al, 2005)) (Figure 1d). Mature Omi with the PDZ domain mutation Y361A (Figure 1c), which cannot interact with C-terminus of WTS (Li et al, 2002), also failed to cleave full-length WTS (Figure 1e).…”

“…We previously reported that STS activates the protease activity of Omi, leading to cell death (Kuninaka et al, 2005). To exclude the possibility that WTS proteolysis induced by STS treatment or mature Omi overexpression is merely a result of cell death, we treated L929 cells with tumor necrosis factor-a (TNF-a) to induce necrosis (Vercammen et al, 1998) and with STS to induce apoptosis.…”

“…We previously found that WTS interacts with Omi (Kuninaka et al, 2005). The C-terminal region of WTS binds directly to the protein/discs-large protein/zonula (PDZ) domain of Omi and enhances its protease activity.…”