A benzenesulfonamide GW8510 rejuvenates mice and yeast through interaction with p21-Activated kinases
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ABSTRACT:
PROVIDER: PRJNA776642 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16646910_1.fastq.gz | Fastqsanger.gz | |||
| SRR16646910_2.fastq.gz | Fastqsanger.gz | |||
| SRR16646911_1.fastq.gz | Fastqsanger.gz | |||
| SRR16646911_2.fastq.gz | Fastqsanger.gz | |||
| SRR16646912_1.fastq.gz | Fastqsanger.gz |
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Project description:Aging, a risk factor for many diseases, is largely attributable to cell senescence and impaired mitochondrial function. Here, we used connectivity map (CMAP) to predict the anti-aging effects of drugs based on age-related transcriptomic signatures. We found the kinase inhibitor GW8510 can extend lifespan of yeast, and C57BL/6J or ICR mice by 92.18%, 31.9%, and 142.9%, respectively. Mechanistically, GW8510 can ameliorate cellular senescence by enhancing mitochondrial function, decreasing SA-β-gal staining, p21 and SASP marker expression, and rescues age-related histomorphological changes in mouse hippocampus, heart, kidney and liver. The GW8510 mode of action depends on STE20 (yeast PAK1 homolog), and binds to PAK1 with Kd of 0.82 μM. The crystal structure shows that GW8510 binds to the PAK1 ATP binding pocket. Furthermore, inhibition of PAKs can delay the effects of aging in mice. This work provides a valuable resource for mechanistic aging studies and suggests strong clinical potential for GW8510.
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Project description:Signaling from the Rho family small GTPases controls a wide range of signaling outcomes. Key among the downstream effectors for many of the Rho GTPases are the p21-activated kinases, or PAK group. The PAK family comprises two types, the type I PAKs (PAK1, 2 and 3) and the type II PAKs (PAK4, 5 and 6), which have distinct structures and mechanisms of regulation. In this review, we discuss signal transduction from Rho GTPases with a focus on the type II PAKs. We discuss the role of PAKs in signal transduction pathways and selectivity of Rho GTPases for PAK family members. We consider the less well studied of the Rho GTPases and their PAK-related signaling. We then discuss the molecular basis for kinase domain recognition of substrates and for regulation of signaling. We conclude with a discussion of the role of PAKs in cross talk between Rho family small GTPases and the roles of PAKs in disease.
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Project description:Over the last three decades, p21-activated kinases (PAKs) have emerged as prominent intracellular nodular signaling molecules in cancer cells with a spectrum of cancer-promoting functions ranging from cell survival to anchorage-independent growth to cellular invasiveness. As PAK family members are widely overexpressed and/or hyperactivated in a variety of human tumors, over the years PAKs have also emerged as therapeutic targets, resulting in the development of clinically relevant PAK inhibitors. Over the last two decades, this has been a promising area of active investigation for several academic and pharmaceutical groups. Similar to other kinases, blocking the activity of one PAK family member leads to compensatory activity on the part of other family members. Because PAKs are also activated by stress-causing anticancer drugs, PAKs are components in the rewiring of survival pathways in the action of several therapeutic agents; in turn, they contribute to the development of therapeutic resistance. This, in turn, creates an opportunity to co-target the PAKs to achieve a superior anticancer cellular effect. Here we discuss the role of PAKs and their effector pathways in the modulation of cellular susceptibility to cancer therapeutic agents and therapeutic resistance.
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Project description:The p21-activated kinases (PAKs) are a family of six serine/threonine kinases that act as key effectors of RHO family GTPases in mammalian cells. PAKs are subdivided into two groups: type I PAKs (PAK1, PAK2, and PAK3) and type II PAKs (PAK4, PAK5, and PAK6). Although these groups are involved in common signaling pathways, recent work indicates that the two groups have distinct modes of regulation and have both unique and common substrates. Here, we review recent insights into the molecular level details that govern regulation of type II PAK signaling. We also consider mechanisms by which signal transduction is regulated at the level of substrate specificity. Finally, we discuss the implications of these studies for clinical targeting of these kinases.
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Project description:Each time Saccharomyces cerevisiae cells divide they ensure that both the mother and daughter cell inherit a vacuole by actively transporting a portion of the vacuole into the bud. As the mother cell begins budding, a tubular and vesicular segregation structure forms that is transported into the bud by the myosin V motor Myo2, which is bound to the vacuole-specific myosin receptor, Vac17 (41, 59, 70, 79). Upon arriving in the bud the segregation structure is resolved to found the daughter vacuole. The mechanism that regulates segregation structure resolution in a spatially dependent manner is unknown. In addition to resolving the segregation structure, Vac17 is degraded specifically in the bud to provide directionality to vacuole inheritance. It has been proposed that bud-specific degradation of Vac17 is promoted by proteins localized to or activated solely in the bud (77). The p21-activated kinases (PAKs) Cla4 and Ste20 are localized to and activated in the bud. Here we report that Cla4 is localized to the segregation structure just prior to segregation structure resolution, and cells lacking PAK function fail to resolve the segregation structure. Overexpression of either Cla4 or Ste20 inhibited vacuole inheritance and this inhibition was suppressed by the expression of nondegradable VAC17. Finally, PAK activity was required for Vac17 degradation in late M phase and CLA4 overexpression promoted Vac17 degradation. We propose that Cla4 and Ste20 are bud-specific proteins that play roles in both segregation structure resolution and the degradation of Vac17.
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Project description:The type II p21-activated kinases (PAKs) are key effectors of RHO-family GTPases involved in cell motility, survival, and proliferation. Using a structure-guided approach, we discovered that type II PAKs are regulated by an N-terminal autoinhibitory pseudosubstrate motif centered on a critical proline residue, and that this regulation occurs independently of activation loop phosphorylation. We determined six X-ray crystal structures of either full-length PAK4 or its catalytic domain, that demonstrate the molecular basis for pseudosubstrate binding to the active state with phosphorylated activation loop. We show that full-length PAK4 is constitutively autoinhibited, but mutation of the pseudosubstrate releases this inhibition and causes increased phosphorylation of the apoptotic regulation protein Bcl-2/Bcl-X(L) antagonist causing cell death and cellular morphological changes. We also find that PAK6 is regulated by the pseudosubstrate region, indicating a common type II PAK autoregulatory mechanism. Finally, we find Src SH3, but not ?-PIX SH3, can activate PAK4. We provide a unique understanding for type II PAK regulation.
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Project description:Correct positioning of organelles is essential to eukaryotic cells. Molecular motors transport organelles to their proper destinations, yet little is known about the pathways that define these destinations. In Saccharomyces cerevisiae, the myosin V motor Myo2 binds the vacuole-specific adapter Vac17 to attach to the vacuole/lysosome and initiate transport. After arrival in the bud, Myo2 releases the vacuole, and Vac17 is degraded. However, the mechanisms that spatially regulate this release were not established. In this study, we report that the bud cortex is a landmark that signals a successful delivery of the vacuole to the bud. We demonstrate that upon arrival at the bud cortex, Vac17 is phosphorylated by Cla4. Cla4-dependent phosphorylation is required for the ubiquitylation and subsequent degradation of Vac17 and the release of the vacuole from Myo2. Our study reveals a critical step in the spatial regulation of myosin V-dependent organelle transport and may reveal common mechanisms for how molecular motors accurately deposit cargoes at the correct locations.
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