Advocating asymmetry and the POP-1 paradox: noncanonical Wnt signaling in C. elegans

In this issue of Cell, Kidd and colleagues (Kidd et al., 2005) describe their identification of a novel beta-catenin that functions in noncanonical C. elegans Wnt signaling pathways to specify the different fates of daughter cells produced by asymmetric cell division.     

Yos9p: a sweet-toothed bouncer of the secretory pathway

In this issue of Molecular Cell, Bhamidipati et al., (2005) and Kim et al., (2005), and Szathmary et al. (2005), and demonstrate that Yos9p selectively binds to aberrant glycoproteins in the endoplasmic reticulum (ER) and targets them for destruction through the ER-associated protein degradation pathway.     

Axis formation--beta-catenin catches a Wnt

In this issue of Cell, the Heasman group implicates Wnt11 as a component of the canonical Wnt signaling pathway that specifies Xenopus laevis axis formation (Tao et al., 2005). This important work not only identifies a long-sought-after dorsalizing factor but also highlights the pivotal role of extracellular cofactors in specifying the activation of either canonical or noncanonical Wnt pathways.     

A nose by any other name (should smell as sweetly)

The standard view that the control of mating behavior by pheromones is mediated by the vomeronasal organ, and not by the main olfactory epithelium, has recently been called into question. In this issue of Cell, two independent studies (Boehm et al., 2005; Yoon et al., 2005) examine the inputs from each of these olfactory pathways to a population of neurons that plays a central role in mating behavior.     

The garden of forking paths: recycling, signaling, and degradation

Three recent papers in Developmental Cell (by Yamamoto et al., Choi et al., and Sigismund et al.) show that the endocytic route of internalization can determine whether signaling receptors are degraded or recycled, and whether they initiate signaling from an endosomal platform. However, the same route can serve opposite functions in different signaling pathways: there is no "unifying theory" of trafficking.     

Regulation of the Wnt/beta-catenin pathway by redox signaling

Although it is well established that reactive oxygen species (ROS) can function as intracellular messengers, the mechanism of ROS dependent signaling is largely unknown (Rhee et al.,2005). In a recent paper in Nature Cell Biology, Funato et al. (2006) demonstrate that ROS can modulate signaling by the Wnt/beta-catenin pathway. This work provides interesting new insight into cross-talk between redox and Wnt/beta-catenin signaling in normal physiology and cancer.     

Mapping out starvation responses

What are the pathways that underlie the coordinated responses of an organism to well-fed and food-deprived states? A report in this issue of Cell Metabolism suggests that starvation functions via a muscarinic acetylcholine receptor to activate MAP kinase signaling in the pharyngeal muscle of C. elegans (You et al., 2006).     

The high road and the low road: trafficking choices in plants

Polar transport of the signaling molecule auxin is critical for plant development and depends on both the polar distribution of auxin efflux carriers, which pump auxin out of the cell and the alignment of these polarized cells. Two papers in this issue of Cell (Michniewicz et al., 2007; Jaillais et al., 2007) address how polar transport of these carriers occurs and describe the endosomal pathways involved.     

If the prophet does not come to the mountain: dynamics of signaling complexes in NF-kappaB activation

Recruitment of the NF-kappaB-activating IKK signaling complex to the TNF receptor is shown to be driven by induced binding of NEMO, a regulatory component of this complex, to K63-linked polyubiquitin chains attached to RIP1, a receptor-associated adaptor protein (Ea et al., 2006 [in a recent issue of Molecular Cell]; Li et al., 2006; Wu et al., 2006a).     

Scube activity is necessary for Hedgehog signal transduction in vivo

The Hedgehog (HH) signaling pathway is a central regulator of embryonic development, controlling the pattern and proliferation of a wide variety of organs. Previous studies have implicated the secreted protein, Scube2, in HH signal transduction in the zebrafish embryo (Hollway et al., 2006; Kawakami et al., 2005; Woods and Talbot, 2005) although the nature of the molecular function of Scube2 in this process has remained undefined. This analysis has been compounded by the fact that removal of Scube2 activity in the zebrafish embryo leads to only subtle defects in HH signal transduction in vivo (Barresi et al., 2000; Hollway et al., 2006; Ochi and Westerfield, 2007; van Eeden et al., 1996; Wolff et al., 2003). Here we present the discovery of two additional scube genes in zebrafish, scube1 and scube3, and demonstrate their roles in facilitating HH signal transduction. Knocking down the function of all three scube genes simultaneously phenocopies a complete loss of HH signal transduction in the embryo, revealing that Scube signaling is essential for HH signal transduction in vivo. We further define the molecular role of scube2 in HH signaling.     

Alternative mitochondrial fuel extends life span

In this issue of Cell Metabolism, Ristow and colleagues (Zarse et?al., 2012) elucidate a conserved mechanism through which reduced insulin-IGF1 signaling activates an AMP-kinase-driven metabolic shift toward oxidative proline metabolism. This, in turn, produces an adaptive mitochondrial ROS signal that extends worm life span. These findings further bolster the concept of mitohormesis as a critical component of conserved aging and longevity pathways.     

ROS: really involved in oxygen sensing

The role of reactive oxygen species (ROS) in the cellular response to cellular oxygen sensing has been controversial. Three papers in this issue of Cell Metabolism (Brunelle et al., Guzy et al., 2005; Mansfield et al., 2005) used genetic tools to establish that ROS produced by mitochondria are required for the normal induction of HIF (hypoxia-inducible factor), which is a master regulator of oxygen-sensitive gene expression, by low oxygen.     

Involvement of HLS1 in sugar and auxin signaling in Arabidopsis leaves

Sugar regulates a variety of genes and controls plant growth and development similarly to phytohormones. As part of a screen for Arabidopsis mutants with defects in sugar-responsive gene expression, we identified a loss-of-function mutation in the HOOKLESS1 (HLS1) gene. HLS1 was originally identified to regulate apical hook formation of dark-grown seedlings (Lehman et al., 1996, Cell 85: 183-194). In hls1, sugar-induced gene expression in excised leaf petioles was more sensitive to exogenous sucrose than that in the wild type. Exogenous IAA partially repressed sugar-induced gene expression and concomitantly activated some auxin response genes such as AUR3 encoding GH3-like protein. The repression and the induction of gene expression by auxin were attenuated and enhanced, respectively, by the hls1 mutation. These results suggest that HLS1 plays a negative role in sugar and auxin signaling. Because AUR3 GH3-like protein conjugates free IAA to amino acids (Staswick et al., 2002, Plant Cell 14: 1405-1415; Staswick et al., 2005, Plant Cell 17: 616-627), enhanced expression of GH3-like genes would result in a decrease in the free IAA level. Indeed, hls1 leaves accumulated a reduced level of free IAA, suggesting that HLS1 may be involved in negative feedback regulation of IAA homeostasis through the control of GH3-like genes. We discuss the possible mechanisms by which HLS1 is involved in auxin signaling for sugar- and auxin-responsive gene expression and in IAA homeostasis.     

Rehabilitation of a contract killer: caspase-3 directs stem cell differentiation

Activation of caspase-3 is generally acknowledged as a penultimate step in apoptotic cell death pathways. Two studies in this issue of Cell Stem Cell (Fujita et al., 2008; Janzen et al., 2008) provide compelling data to demonstrate that caspase-3 is also a conserved inductive cue for stem cell differentiation.     

A skeleton of the human protein interactome

In this issue of Cell, Wanker and colleagues (Stelzl et al., 2005) present a large-scale two-hybrid map of more than 3000 putative human protein-protein interactions. These new data will serve as an important source of information regarding individual protein partners and offer preliminary insight into the global molecular organization of human cells.     

Transduction of the chemotactic signal to the actin cytoskeleton of Dictyostelium discoideum

Dictyostelium discoideum amebae chemotax toward folate during vegetative growth and toward extracellular cAMP during the aggregation phase that follows starvation. Stimulation of starving amebae with extracellular cAMP leads to both actin polymerization and pseudopod extension (Hall et al., 1988, J. Cell. Biochem. 37, 285-299). We have identified an actin nucleation activity (NA) from starving amebae that is regulated by cAMP receptors and controls actin polymerization (Hall et al., 1989, J. Cell Biol., in press). We show here that NA from vegetative cells is also regulated by chemotactic receptors for folate. Our studies indicate that NA is an essential effector in control of the actin cytoskeleton by chemotactic receptors. Guided by a recently proposed model for signal transduction from the cAMP receptor (Snaar-Jagalska et al., 1988, Dev. Genet. 9, 215-225), we investigated which of three signaling pathways activates the NA effector. Treatment of whole cells with a commercial pertussis toxin preparation (PT) inhibited cAMP-stimulated NA. However, endotoxin contamination of the PT appears to account for this effect. The synag7 mutation and caffeine treatment do not inhibit activation of NA by cAMP. Thus, neither activation of adenylate cyclase nor a G protein sensitive to PT treatment of whole cells is necessary for the NA response. Actin nucleation activity stimulated with folate is normal in vegetative fgdA cells. However, cAMP suppresses rather than activates NA in starving fgdA cells. This indicates that the components of the actin nucleation effector are present and that a pathway regulating the inhibitor(s) of nucleation remains functional in starving fgdA cells. The locus of the fgdA defect, a G protein implicated in phospholipase C activation, is directly or indirectly responsible for transduction of the stimulatory chemotactic signal from cAMP receptors to the nucleation effector in Dictyostelium.     

Can 1000 reviews be wrong? Actin, alpha-Catenin, and adherens junctions

Coupling between cell adhesion and the actin cytoskeleton is thought to require a stable link between the cadherin-catenin complex and actin that is mediated by alpha-catenin. In this issue of Cell, the Weis and Nelson groups call this static model into question, showing that alpha-catenin can directly regulate actin dynamics (Drees et al., 2005 and Yamada et al., 2005).     

Another job for the talented p120-catenin

Given the complexity of signaling pathways in the cell, it is a mystery how these pathways communicate with one other. In this issue of Cell, Wildenberg et al. (2006) reveal that the key effector molecule p120-catenin can mediate crosstalk between the Rac and Rho signaling pathways.     

Stressed-out mitochondria get MAD

Mechanisms maintaining mitochondrial integrity range from specific repair pathways to wholesale degradation of damaged organelles. A recent study in Molecular Cell (Heo et?al., 2010) adds another mechanism to this mitochondrial homeostasis toolkit: mitochondria-associated protein degradation (MAD) that ultimately directs endoplasmic reticulum-associated protein degradation (ERAD) pathway components to oxidatively stressed mitochondria.