RESUMO
Oncogenic small guanosine triphosphatases (GTPases) are often characterized by a limited set of activating mutations that affect their intrinsic biochemical function, but RHOA-which is frequently mutated in gastric cancer-appears not to have read the instruction manual. Having previously characterized the Y42C RHOA mutation in gastric cancer, in this issue of Science Signaling, Schaefer et al. take on the slightly less common L57V mutation and find that individual RHOA mutations can have different and unpredictable signaling outcomes.
Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Mutação , Transdução de Sinais/genética , Mutação com Ganho de Função , GTP Fosfo-Hidrolases/genética , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
In this issue of Cell Chemical Biology, Liu et al.1 identify TRIM21-mediated ubiquitination of the Hippo pathway kinase MST2, promoting its dimerization and activation. The antidepressant Vilazodone was found to bind to TRIM21, enhancing its activity toward MST2, increasing Hippo activation, and reducing colorectal cancer metastasis.
Assuntos
Neoplasias do Colo , Proteínas Serina-Treonina Quinases , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Via de Sinalização Hippo , Transdução de Sinais , Serina-Treonina Quinase 3 , UbiquitinaçãoRESUMO
Three elements of the Hippo tumor suppressor pathway - MST1/2, SAV1, and RASSF1-6 - share in common a C-terminal interaction motif termed the SARAH domain. Proteins containing this domain are capable of self-association as homodimers and also of trans-association with other SARAH domain containing proteins as well as selected additional proteins that lack this domain. Recently, the association of MST1/2 with itself or with other proteins has been shown to be regulated by phosphorylation at sites near or within the SARAH domain. In this review, we focus on recent findings regarding the regulation of such MST1/2 interactions, with an emphasis on the effects of these events on Hippo pathway activity.
Assuntos
Regulação da Expressão Gênica , Via de Sinalização Hippo/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Complexos Multiproteicos/genética , Proteínas Serina-Treonina Quinases/genética , Serina-Treonina Quinase 3/genética , Sequência de Aminoácidos , Animais , Sítios de Ligação/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Domínios Proteicos , Multimerização Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Homologia de Sequência de Aminoácidos , Serina-Treonina Quinase 3/química , Serina-Treonina Quinase 3/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
Puromycin-sensitive aminopeptidases are found across phyla and are known to regulate the cell-cycle and play a protective role in neurodegenerative disease. PAM-1 is a puromycin-sensitive aminopeptidase important for meiotic exit and polarity establishment in the one-cell Caenorhabditis elegans embryo. Despite conservation of this aminopeptidase, little is known about its targets during development. In order to identify novel interactors, we conducted a suppressor screen and isolated four suppressing mutations in three genes that partially rescued the maternal-effect lethality of pam-1 mutants. Suppressed strains show improved embryonic viability and polarization of the anterior-posterior axis. We identified a missense mutation in wee-1.3 in one of these suppressed strains. WEE-1.3 is an inhibitory kinase that regulates maturation promoting factor. Although the missense mutation suppressed polarity phenotypes in pam-1, it does so without restoring centrosome-cortical contact or altering the cortical actomyosin cytoskeleton. To see if PAM-1 and WEE-1.3 interact in other processes, we examined oocyte maturation. Although depletion of wee-1.3 causes sterility due to precocious oocyte maturation, this effect was lessened in pam-1 worms, suggesting that PAM-1 and WEE-1.3 interact in this process. Levels of WEE-1.3 were comparable between wild-type and pam-1 strains, suggesting that WEE-1.3 is not a direct target of the aminopeptidase. Thus, we have established an interaction between PAM-1 and WEE-1.3 in multiple developmental processes and have identified suppressors that are likely to further our understanding of the role of puromycin-sensitive aminopeptidases during development.
Assuntos
Proteínas de Caenorhabditis elegans , Doenças Neurodegenerativas , Aminopeptidases/genética , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Embrião não Mamífero , Oócitos , Proteínas Serina-Treonina Quinases , Proteínas Tirosina QuinasesRESUMO
Diffuse gastric cancer (DGC) is characterized by frequent missense mutations in the small GTPase RHOA, but the effects of this mutation on enzyme activity and signaling have been widely debated. In this issue, Zhang and colleagues show that the most common RHOA mutation in DGC, encoding RHOAY42C, represents a gain of function; that a mouse model incorporating this mutation in association with loss of the E-cadherin gene CDH1 recapitulates many aspects of DGC; and that rationally designed therapeutics based on our understanding of RHOA signaling are promising agents for treating DGC.See related article by Zhang et al., p. 288.
