Editors' ChoiceStress Pathways

Stress and the RACK

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Science Signaling  11 Nov 2008:
Vol. 1, Issue 45, pp. ec384
DOI: 10.1126/scisignal.145ec384

Arimoto et al. report cross-talk between stress response pathways through effects on a scaffolding protein, RACK1, that may have relevance to cancer therapies. Some types of stress, like hypoxia, cause formation of cytoplasmic stress granules in which stalled translation complexes are sequestered to avoid production of misfolded proteins. Other types of stress, like x-rays or drugs that cause DNA damage, mainly cause cell death by activating signaling through stress-activated protein kinases. Arimoto screened for proteins that interacted with MEKK4 (a mitogen-activated protein kinase kinase kinase also known as MTK1)—which functions in activation of stress-activated protein kinases and thus promotes stress-induced apoptosis—and identified the G protein β subunit-like scaffold protein RACK1. Depletion of RACK1 from human embryonic kidney 293 cells inhibited activation of MTK1, as detected with antibodies that recognized the phosphorylated, active form of MTK1. Studies of localization of the proteins by immunofluorescence microscopy revealed that MTK and RACK1 were present in the cytoplasm of unstimulated cells. However, stress treatments that caused formation of stress granules resulted in association of RACK1, but not MTK1, with the granules. When both types of stress signals (one inducing formation of stress granules and one promoting apoptosis) were applied, such sequestration of RACK1 into granules inhibited activation of MTK1 and apoptosis of the cells. The authors point out that cells in solid tumors suffer from hypoxia, which causes formation of stress granules. Some anticancer therapies, like radiation and certain anticancer drugs, act by causing DNA damage and apoptosis of the cancer cells. Thus, the sequestration of RACK1 in such cancer cells could contribute to their resistance to anticancer therapies.

K. Arimoto, H. Fukuda, S. Imajoh-Ohmi, H. Saito, M. Takekawa, Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways. Nat. Cell Biol. 10, 1324-1332 (2008). [PubMed]

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