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  • In cardiomyocytes mechanical stress builds up via FAs

    2022-07-02

    In cardiomyocytes mechanical stress builds up via FAs and the related costamere structures, and excessive stress can cause cardiac hypertrophy. Cardoso et al. (2016) report a comprehensive study that demonstrates the link between stress-induced FAK activation and a FAK-mediated initiation of a transcriptional program for cardiac hypertrophy. The authors previously showed that cyclic stretch activates FAK in cardiomyocytes (Domingos et al., 2002) and that the induced FAK activity constitutes an upstream regulatory signal for MEF2 and JNK to induce c-Jun activity (Nadruz et al., 2005), a known activator of the hypertrophic program induced by mechanical stress in cardiomyocytes. In Cardoso et al. (2016), the authors demonstrate that cyclic stretch causes the accumulation of FAK in the nucleus. They show that in the nucleus, FAK interacts with the MEF2 transcription factor and the interaction is mediated by the FAK C-terminal focal adhesion targeting (FAT) domain and the N-terminal MADS/MEF2 region of MEF2. The authors go on to solve a crystal structure of the complex and obtain a rather complex assembly in the asymmetric unit, which contains 2 MEF dimers and 3 FAT domains. Using SAXS and mutagenesis, Cardoso et al. dissect the relevant unit to a 2:1 MEF2:FAT complex, where the 2 MEF2 chains are tightly folded into one integral domain, as seen in previous MEF2 dimers. The FAT interaction surface on MEF2 is opposite to the DNA binding domain and the authors confirm that MEF2 can bind FAK and DNA simultaneously. Finally, Cardoso et al. show that residues observed at the interface in the crystal structure are responsible for FAK association with MEF2 on the c-Jun promoter in cardiomyocytes from overloaded cc-5013 and this interaction enhances the activity of MEF2, driving transcription of the c-Jun gene. Together, this provides a comprehensive study on mechanisms linking mechanical overload with cardiac hypertrophy. It also provides the first high-resolution structural information of a FAK function in the nucleus. The increasing number of reports on FAK functions in the nucleus portrays a very diverse and complex picture of how FAK can affect gene transcription. Different regions of FAK appear to carry out different types of functions. The N-terminal FERM domain of FAK is involved in promoting ubiquitination of nuclear factors, as reported for p53 and GATA4, resulting in their degradation (Lim et al., 2008, Lim et al., 2012). Interestingly, another FERM containing protein, merlin, is reported to inhibit nuclear E3 ubiquitin ligase (Li et al., 2010), but it remains to be seen whether the FAK function is in any way related to this. On the other hand, direct regulatory interactions with nuclear factors are achieved via the C-terminal FAT domain of FAK, as reported for interactions with MEF2 (Cardoso et al., 2016) and MBD2 (Luo et al., 2009). Indeed, it seems that the FAT domain of FAK is rather flexible in engaging binding partners, since its interaction mode with paxillin LD motifs, for example, is rather different from the one with MEF2. There is also variability with respect to the requirement for kinase activity. For FERM-mediated ubiquitination of transcription factors kinase activity is dispensable (Lim et al., 2008, Lim et al., 2012), whereas activation of an immunosuppressive transcriptional program in cancer cells requires kinase activity (Serrels et al., 2015). Several important questions remain, in particular those related to mechanisms that result in FAK accumulation in the nucleus. In the case of mechanical stress, FAK phosphorylation appears to correlate with its nuclear localization. However, whether FAK activation is causative of nuclear transport is unclear. Indeed, it is puzzling how activated FAK engages in FAT-mediated interactions. Overload-induced FAK activation in myocytes results in association with the Src kinase and phosphorylation of FAK on multiple sites, including Y925 in the FAT domain (Domingos et al., 2002). The latter is required for binding to the Grb2 adaptor protein, which induces Grb2/Sos-mediated Ras/MAPK signaling. On the other hand, it is believed that Y925 phosphorylation and Grb2 binding require release and melting of helix α1 from the FAT four-helix bundle (Mohanty and Bhatnagar, 2016). This is shown to negatively affect binding of FAT to two paxillin binding sites, one of them involving, as with the MEF2 interaction, helices α2 and α3 of the FAT domain. This would suggest that at some point between mechanical activation of FAK in adhesion sites and nuclear localization, Grb2 should dissociate from the FAT domain to allow MEF2 binding (Figure 1). Intriguingly, opposite to the situation in cardiomyocytes, in endothelial cells FAK inhibition appears to trigger nuclear localization; however, here the mechanism is also unclear.