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Abl and Arg mediate cysteine cathepsin secretion to facilitate melanoma invasion and metastasis

2018-02-20T10:55:14-08:00

The incidence of melanoma is increasing, particularly in young women, and the disease remains incurable for many because of its aggressive, metastatic nature and its high rate of resistance to conventional, targeted, and immunological agents. Cathepsins are proteases that are critical for melanoma progression and therapeutic resistance. Intracellular cathepsins cleave or degrade proteins that restrict cancer progression, whereas extracellular cathepsins directly cleave the extracellular matrix and activate proinvasive proteases in the tumor microenvironment. Cathepsin secretion is markedly increased in cancer cells. We investigated the signaling pathways leading to increased cathepsin secretion in melanoma cells. We found that the nonreceptor tyrosine kinases Abl and Arg (Abl/Arg) promoted the secretion of cathepsin B and cathepsin L by activating transcription factors (namely, Ets1, Sp1, and NF-B/p65) that have key roles in the epithelial-mesenchymal transition (EMT), invasion, and therapeutic resistance. In some melanoma cell lines, Abl/Arg promoted the Ets1/p65-induced secretion of cathepsin B and cathepsin L in a kinase-independent manner, whereas in other melanoma lines, Abl/Arg promoted the kinase-dependent, Sp1/Ets1/p65–mediated induction of cathepsin L secretion and the Sp1/p65-mediated induction of cathepsin B secretion. As an indication of clinical relevance, the abundance of mRNAs encoding Abl/Arg, Sp1, Ets1, and cathepsins was positively correlated in primary melanomas, and Abl/Arg-driven invasion in culture and metastasis in vivo required cathepsin secretion. These data suggest that drugs targeting Abl kinases, many of which are FDA-approved, might inhibit cathepsin secretion in some melanomas and potentially other aggressive cancers harboring activated Abl kinases.




The intracellular pyrimidine 5'-nucleotidase NT5C3A is a negative epigenetic factor in interferon and cytokine signaling

2018-02-20T10:55:14-08:00

The enzyme pyrimidine 5'-nucleotidase (NT5C3A), which mediates nucleotide catabolism, was previously thought to be restricted to blood cells. We showed that expression of the gene encoding NT5C3A was induced by type I interferons (IFNs) in multiple cell types and that NT5C3A suppressed cytokine production through inhibition of the nuclear factor B (NF-B) pathway. NT5C3A expression required both an intronic IFN-stimulated response element and the IFN-stimulated transcription factor IRF1. Overexpression of NT5C3A, but not of its catalytic mutants, suppressed IL-8 production by HEK293 cells. Whereas knockdown of NT5C3A enhanced tumor necrosis factor (TNF)–stimulated IL-8 production, it reduced the IFN-mediated suppression of Il8 expression. Overexpression of NT5C3A increased the abundance of NAD+ and the activation of the sirtuins SIRT1 and SIRT6, which are NAD+-dependent deacetylases. NT5C3A-stimulated sirtuin activity resulted in deacetylation of histone H3 and the NF-B subunit RelA (also known as p65), both of which were associated with the proximal region of the Il8 promoter, thus repressing the transcription of Il8. Together, these data identify an anti-inflammatory pathway that depends on the catalytic activity of NT5C3A and functions as a negative feedback regulator of inflammatory cytokine signaling.




Condemned by metabolism

2018-02-20T10:55:14-08:00

The kinase RIP3 increases aerobic flux to produce reactive oxygen species, which enhances necrosome formation and necroptosis.




A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate {beta}-arrestin-biased signaling

2018-02-20T10:55:14-08:00

The calcium-sensing receptor (CaSR) is a G protein–coupled receptor (GPCR) that signals through Gq/11 and Gi/o to stimulate cytosolic calcium (Ca2+i) and mitogen-activated protein kinase (MAPK) signaling to control extracellular calcium homeostasis. Studies of loss- and gain-of-function CASR mutations, which cause familial hypocalciuric hypercalcemia type 1 (FHH1) and autosomal dominant hypocalcemia type 1 (ADH1), respectively, have revealed that the CaSR signals in a biased manner. Thus, some mutations associated with FHH1 lead to signaling predominantly through the MAPK pathway, whereas mutations associated with ADH1 preferentially enhance Ca2+i responses. We report a previously unidentified ADH1-associated R680G CaSR mutation, which led to the identification of a CaSR structural motif that mediates biased signaling. Expressing CaSRR680G in HEK 293 cells showed that this mutation increased MAPK signaling without altering Ca2+i responses. Moreover, this gain of function in MAPK activity occurred independently of Gq/11 and Gi/o and was mediated instead by a noncanonical pathway involving β-arrestin proteins. Homology modeling and mutagenesis studies showed that the R680G CaSR mutation selectively enhanced β-arrestin signaling by disrupting a salt bridge formed between Arg680 and Glu767, which are located in CaSR transmembrane domain 3 and extracellular loop 2, respectively. Thus, our results demonstrate CaSR signaling through β-arrestin and the importance of the Arg680-Glu767 salt bridge in mediating signaling bias.




Coordinating the overall stomatal response of plants: Rapid leaf-to-leaf communication during light stress

2018-02-20T10:55:14-08:00

The plant canopy functions as an aerial array of light-harvesting antennas. To achieve maximal yield, each leaf within this array and the array as a whole need to rapidly adjust to naturally occurring fluctuations in light intensity and quality. Excessive light stress triggers the closing of pores in leaves called stomata to minimize moisture loss. We found that different leaves within the canopy of an Arabidopsis thaliana plant, including leaves not directly exposed to light, coordinated stomatal closure in response to light stress by sending and receiving rapid systemic signals. This response required the plant hormones abscisic acid and jasmonic acid and was mediated by a rapid autopropagating wave of reactive oxygen species (ROS) production. Furthermore, this response depended on the function of genes encoding the ROS-generating NADPH oxidase RBOHD and various stomatal regulators, such as the anion channel SLAC1, GHR1 (guard cell hydrogen peroxide resistant 1), and lipoxygenase 1 (LOX1). Our findings reveal that plants function as highly dynamic and coordinated organisms, optimizing the overall response of their canopies to fluctuating light intensities.