H11/HspB8 and Its Herpes Simplex Virus Type 2 Homologue ICP10PK Share Functions That Regulate Cell Life/Death Decisions and Human Disease
Figure 3
H11/HsPB8 causes growth arrest and melanoma cell death through distinct TAK1-regulated pathways. (a) Schematic representation of H11/HspB8-induced growth arrest involves β-catenin phosphorylation by the activated TAK1. (b) GST-β-catenin phosphorylated when mixed with cell extracts containing H11/HspB8-activated TAK1 is ubiquitylated causing its degradation (*). Ubiquitylation is not seen when GST-β-catenin is mixed with cell extracts that lack H11/HspB8 and therefore pTAK1. (c) H11/HspB8 induces different death pathways in the genetically diverse melanoma cells A375 and A2058 that initiate with TAK1 activation. In A375 cells, the TAK1/p38MAPK pathway activates caspase-3/7 to cause apoptosis. In A2058 cells, the TAK1/p38MAPK pathway activates caspase-3, but TAK1 also activates caspase-1 through ASC upregulation and upregulates Beclin-1 through mTOR phosphorylation at S2481 (pmTORS2481). Caspase-1 cleaves Beclin-1 to promote apoptosis, but Beclin-1 also contributes to cell death through still unknown tumor suppressor functions. The W51C mutant of H11/HspB8 has dominant-negative activity. It inhibits the death-inducing potential of the wild-type H11/HspB8 by inhibiting caspase activation through the activation of the B-Raf/MEK/ERK pathway [33].
