Notch signaling: a different sort makes the cut

Notch signaling is regulated by ubiquitination of the receptor and its extracellular ligands. New studies reveal distinct ubiquitination-dependent endosomal sorting pathways in which ligand-bound Notch is activated while unliganded Notch is recycled or degraded, facilitating signaling while preventing inappropriate activation of unstimulated receptors.     

Jun N-terminal kinase signaling makes a face

decapentaplegic (dpp), the Drosophila ortholog of BMP 2/4, directs ventral adult head morphogenesis through expression in the peripodial epithelium of the eye-antennal disc. This dpp expressing domain exerts effects both on the peripodial epithelium, and the underlying disc proper epithelium. We have uncovered a role for the Jun N-terminal kinase (JNK) pathway in dpp-mediated ventral head development. JNK activity is required for dpp's action on the disc proper, but in the absence of dpp expression, excessive JNK activity is produced, leading to specific loss of maxillary palps. In this review we outline our hypotheses on how dpp acts by both short range and longer range mechanisms to direct head morphogenesis and speculate on the dual role of JNK signaling in this process. Finally, we describe the regulatory control of dpp expression in the eye-antennal disc, and pose the problem of how the various expression domains of a secreted protein can be targeted to their specific functions.     

Invasive species: customs intercepts reveal what makes a good ant stowaway

A recent analysis of decades of US customs intercepts has revealed which ants had an opportunity to become established in the United States, providing insights into the requisite traits that enable an ant species to become a successful invader.     

Notch signaling: numb makes the difference

During Drosophila sensory organ precursor cell development, Numb segregates asymmetrically and functions as a cell fate determinant. Recent work now demonstrates in vivo that Numb inactivates Notch by promoting its endocytosis.     

Notch signaling: endocytosis makes delta signal better

Endocytosis of cell surface receptors is involved in down-regulation of receptor activity. Recent findings indicate that, paradoxically, endocytosis of a membrane-spanning ligand may up-regulate receptor activity: the zebrafish E3 ligase Mind bomb promotes the endocytosis of Delta and is required for efficient activation of Notch.     

Intracellular regulation of cell signaling cascades: how location makes a difference

Organelles such as endosomes and the Golgi apparatus play a critical role in regulating signal transmission to the nucleus. Recent experiments have shown that appropriate positioning of these organelles within the intracellular space is critical for effective signal regulation. To understand the mechanism behind this observation, we consider a reaction-diffusion model of an intracellular signaling cascade and investigate the effect on the signaling of intracellular regulation in the form of a small release of phosphorylated signaling protein, kinase, and/or phosphatase. Variational analysis is applied to characterize the most effective regions for the localization of this intracellular regulation. The results demonstrate that signals reaching the nucleus are most effectively regulated by localizing the release of phosphorylated substrate protein and kinase near the nucleus. Phosphatase release, on the other hand, is nearly equally effective throughout the intracellular space. The effectiveness of the intracellular regulation is affected strongly by the characteristics of signal propagation through the cascade. For signals that are amplified as they propagate through the cascade, reactions in the upstream levels of the cascade exhibit much larger sensitivities to regulation by release of phosphorylated substrate protein and kinase than downstream reactions. On the other hand, for signals that decay through the cascade, downstream reactions exhibit larger sensitivity than upstream reactions. For regulation by phosphatase release, all reactions within the cascade show large sensitivity for amplified signals but lose this sensitivity for decaying signals. We use the analysis to develop a simple model of endosome-mediated regulation of cell signaling. The results demonstrate that signal regulation by the modeled endosome is most effective when the endosome is positioned in the vicinity of the nucleus. The present findings may explain at least in part why endosomes in many cell types localize near the nucleus.     

Paternity cues and mating opportunities: what makes fathers good?

Human males provide facultative paternal investment to their offspring; that is, the male care is not necessary for the survival of his offspring. It is expected that the degree of male investment (1) increases with growing paternity certainty, (2) increases when investment increases the survival and later reproductive prospect of offspring and (3) declines when there are opportunities to mate with multiple females. Using a large sample of adult offspring and their fathers (n = 245), we first investigated the role of two factors possibly involved in the assessment of paternity and subsequently regulating the level of paternal investment: (a) father–child facial resemblance and (b) assortative mating for eye colour. Second, because mating opportunities are inversely related to paternal investment, we also investigated how male facial attractiveness (a cue of mate opportunities) correlates with paternal investment. In line with paternal investment theory, male investment positively correlated with offspring facial resemblance. However, paternal investment were neither higher among blue-eyed couples, nor there were preferences of blue-eyed men to marry with blue-eyed women. Moreover, father facial attractiveness was unrelated to paternal investment. These results indicate that resemblance between offspring and their fathers still plays an important role in paternal investment decision later in offspring’s life.     

CO-metal interaction: Vital signaling from a lethal gas

The past few years have witnessed intense research into the biological significance of carbon monoxide (CO) as an essential signaling mediator in cells and tissues. To transduce the signal properly, CO must react selectively with functional and structural proteins containing moieties that show preferred reactivity towards this gaseous molecule. This selectivity is exemplified by the interaction of CO with iron- and heme-dependent proteins, although systems containing other transition metals can potentially become a preferential target for CO. Notably, transition metal carbonyls, which carry and liberate CO, are also emerging as a pharmacological tool to mimic the bioactivity of endogenously generated CO. Thus, exploring how CO binding to metal complexes is translated into a cytoprotective function is a challenging task and might open up opportunities for therapeutic applications based on CO delivery.     

Evolution of influence: signaling in a lycaenid-ant interaction

Some phytophagous insects gain defense from natural enemies by associating with otherwise potentially harmful top predators. Many lycaenid butterfly caterpillars are involved in such interactions with ants: larvae provide carbohydrate rewards from the dorsal nectary organ (DNO) to associated ants in return for protection from natural enemies. The stability of these interactions involves signals that identify the lycaenid caterpillar as a mutualist. However, larvae of some lycaenid species, such as Lycaena xanthoides, are found in close association with ants but do not possess the reward producing DNO. Evaluating the relationship in a phylogenetic framework, we show that the association between L. xanthoides and ants likely evolved from a non-ant-associated ancestor. Behavioral trials also show that L. xanthoides larvae are capable of influencing ant behavior to increase ant tending when faced with a simulated predator attack, without providing DNO-derived rewards to ant associates. These results demonstrate that the DNO is not necessary to maintain associations between lycaenid larvae and ants. Third-party interactions may affect the evolution of mutualisms and consideration of underlying evolutionary history is necessary to understand contemporary species associations.     

Wnt signaling: the good and the bad

Since the first Wnt gene was identified in 1982, the functions and mechanisms of Wnt signaling have been extensively studied. Wnt signaling is conserved from invertebrates to vertebrates and regulates early embryonic development as well as the homeostasis of adult tissues. In addition, both embryonic stem cells and adult stem cells are regulated by Wnt signaling. Deregulation of Wnt signaling is associated with many human diseases, particularly cancers. In this review, we will discuss in detail the functions of many components involved in the Wnt signal transduction pathway. Then, we will explore what is known about the role of Wnt signaling in stem cells and cancers.     

Switching Akt: from survival signaling to deadly response

Akt, a protein kinase hyperactivated in many tumors, plays a major role in both cell survival and resistance to tumor therapy. A recent study, 1 along with other evidences, shows interestingly, that Akt is not a single‐function kinase, but may facilitate rather than inhibit cell death under certain conditions. This hitherto undetected function of Akt is accomplished by its ability to increase reactive oxygen species and to suppress antioxidant enzymes. The ability of Akt to down‐regulate antioxidant defenses uncovers a novel Achilles' heel, which could be exploited by oxidant therapies in order to selectively eradicate tumor cells that express high levels of Akt activity.     

Insulin signaling: inositol phosphates get into the Akt

An acute but transient response to insulin is essential for glucose homeostasis in mammals. Chakraborty et?al. (2010) uncover a new feedback mechanism regulating insulin signaling. They show that the inositol pyrophosphate IP7, which is produced in response to insulin, inhibits the Akt kinase, a primary effector of insulin signaling.     

Akt isoform-specific signaling in breast cancer

Numerous studies have shown that Akt isoforms promote tumorigenesis by enhancing cancer cell survival and growth, and it is well established that signaling through the Akt upstream regulator PI 3-K enhances cancer cell migration. Therefore, it is conventionally accepted that PI 3-K/Akt pathway promotes tumor formation and metastasis. A few years ago, studies from several laboratories added a new layer to the pleiotropic effects of Akt function by showing that the Akt1 isoform inhibits breast cancer cell migration and invasion, whereas Akt2 promotes these phenotypes. These studies challenged the dogma and identified non-redundant functions of Akt isoforms in cancer progression. The identification of palladin as an Akt1-specific substrate in our recently published work has exemplified distinct Akt isoform-specific signaling in breast cancer. Here, we review these findings and discuss the implications for the understanding of the mechanistic basis for designing more effective anti-cancer therapeutics targeting the Akt pathway.     

Cell-type-specific regulation of raft-associated Akt signaling

20S-protopanaxadiol (aPPD) is a metabolite of ginseng saponins, which is reported to be pro-apoptotic in some cells but anti-apoptotic in neuronal cells by regulating Akt signaling. Owing to its cholesterol-like structure, we hypothesized that aPPD may regulate Akt signaling by interacting with lipid rafts. Here, we compared Akt signaling in glioblastoma U87MG and neuroblastoma Neuro-2a cells treated with aPPD. aPPD did not change Akt activity in the total plasma membranes of each cell type, but drastically altered the activity of raft-associated Akt. Strikingly, Akt activity was decreased in the rafts of U87MG cells but increased in N2a cells by aPPD through regulating raft-associated dephosphorylation. The bidirectional regulation of raft-associated Akt signaling by aPPD enhanced the chemotoxicity of Paclitaxel or Vinblastine in U87MG cells but attenuated the excitotoxicity of N-methyl--aspartate in N2a cells. Our results demonstrated that the activity of raft-associated but not total membrane Akt determines its cellular functions. Lipid rafts differ in different types of cells, which allows for the possibility of cell-type-specific targeting for which aPPD might prove to be a useful agent.     

mTOR and Akt signaling in cancer: SGK cycles in

In a recent issue of Molecular Cell, Hong et al. (2008) describe an alternative mechanism by which mTOR promotes cell-cycle progression; it phosphorylates and activates SGK, which in turn phosphorylates the cell-cycle inhibitor p27, promoting its cytoplasmic retention.     

And Lophotrochozoa makes three: Notch/Hes signaling in annelid segmentation

Segmentation is unquestionably a major factor in the evolution of complex body plans, but how this trait itself evolved is unknown. Approaching this problem requires comparing the molecular mechanisms of segmentation in diverse segmented and unsegmented taxa. Notch/Hes signaling is involved in segmentation in sequentially segmenting vertebrates and arthropods, as judged by patterns of expression of one or more genes in this network and by the disruption of segmental patterning when Notch/Hes signaling is disrupted. We have previously shown that Notch and Hes homologs are expressed in the posterior progress zone (PPZ), from which segments arise, in the leech Helobdella robusta, a sequentially segmenting lophotrochozoan (phylum Annelida). Here, we show that disrupting Notch/Hes signaling disrupts segmentation in this species as well. Thus, Notch/Hes functions in either the maintenance of the PPZ and/or the patterning processes of segmentation in representatives of all three superphyla of bilaterally symmetric animals. These results are consistent with two evolutionary scenarios. In one, segmentation was already present in the ancestor of all three superphyla. In the other, Notch/Hes signaling functioned in axial growth by terminal addition in an unsegmented bilaterian ancestor, and was subsequently exapted to function in segmentation as that process evolved independently in two or more taxa.