Regulation of stress granule dynamics by Grb7 and FAK signalling pathway

Abstract

Cells form stress granules (SGs) in response to environmental stresses, which constitute cytoplasmic domains where mRNAs are stored and translation is halted. Although several components are found in SGs, it is poorly understood as to how SGs are formed and dissolved. We identified growth factor receptor‐bound protein 7 (Grb7), an RNA‐binding, translational regulator, as an integral component of SGs, which directly interacts with Hu antigen R (HuR) and is required for cells to form SGs. When stress is terminated, Grb7 is hyperphosphorylated by focal adhesion kinase (FAK), loses its ability to directly interact with HuR and is dissociated from SG components, thereby disrupting SGs in recovering cells. Consistently, dominant‐negative hypophospho mutants of FAK and Grb7 significantly attenuate SG disassembly during recovery. FAK activation followed by its phosphorylating Grb7 constitutes a cell‐autonomous signalling pathway that regulates the disassembly of SGs and translational stimulation during recovery. This is the first reported pathway actively regulating the dynamics of SGs.

mRNP granules

“…This later phenomenon also holds true for specific mRNAs, which exit stress granules and enter translation during the recovery phase. 62,63 Dendritic P-bodies also disassemble upon synaptic activation, 15 which may reflect entry of mRNAs into translation. mRNP granules could also be disassembled via mRNA decay, which is most likely relevant to P-bodies, given their enrichment for the decay machinery, the detection of mRNA decay intermediates within, and a correlative increase in P-body numbers when hard to degrade substrates are present.…”

Grb7 - A Newly Emerging Target in Pancreatic Cancer

“…For instance, mouse Grb7 has been shown to interact with HuR (Tsai et al, 2008), an RNA-binding protein important in regulation of nuclear-to-cytoplasmic shuttling of mRNA (Doller et al, 2008). The Grb7-HuR interaction is found to be mediated by the N-terminal domain of Grb7 (Tsai et al, 2008). Moreover, mouse Grb7 is also found to bind RNA via its proline rich Nterminal domain (Doller et al, 2008).…”

“…Recently, however, experiments have indicated novel potential binding partners. For instance, mouse Grb7 has been shown to interact with HuR (Tsai et al, 2008), an RNA-binding protein important in regulation of nuclear-to-cytoplasmic shuttling of mRNA (Doller et al, 2008). The Grb7-HuR interaction is found to be mediated by the N-terminal domain of Grb7 (Tsai et al, 2008).…”

“…Grb7 is an intracellular protein primarily found in the cytosol though it is localised to focal contacts, mitochondria and cell membrane under certain circumstances (Shen et al, 2004). In addition, Grb7 is found to be localized as an integral component of stress granules (Tsai et al, 2008). It is found to be conserved amongst mammals as the gene and its protein product are found in a number of mammalian species with high sequence 401 homology.…”

“…The most recent data suggest that Grb7 is able to recruit RasGTPases leading to phosphorylation of ERK1/2 and cell proliferation (Chu et al, 2010). Another set of studies have identified interactions between Grb7, RNA and the RNA-binding protein HuR leading to the proposal that Grb7 can act at the level of translational regulation (Tsai et al, 2007(Tsai et al, , 2008. (Pero et al, 2003;Golubovskaya et al, 2009).…”