Heterotrimeric G proteins: new tricks for an old dog

Heterotrimeric G proteins are well known for their function in signal transduction downstream of seven transmembrane receptors. More recently, however, genetic analysis in C. elegans and in Drosophila has revealed a second, essential function of these molecules in positioning the mitotic spindle and attaching microtubules to the cell cortex. Five new publications in Cell (Afshar et al., 2004; Du and Macara, 2004 [this issue of Cell]; Hess et al., 2004), Developmental Cell (Martin-McCaffrey et al., 2004), and Current Biology (Couwenbergs et al., 2004) show that this function is conserved in vertebrates and--like the classical pathway--involves cycling of G proteins between GDP and GTP bound conformations.     

Fueling synapses

The transmission of information across neuronal synapses is an energetically taxing business. Sheng and colleagues monitored the localization of mitochondria following different levels of synaptic activation and discovered that these organelles change their distribution in interesting ways, stalling near synapses when neurons are activated and increasing their movement when neurons are silent (Li et al., 2004 [this issue of Cell]).     

Gi Irks GIRKs.

G protein-activated potassium channels (GIRKs), monitored with the temporal and molecular resolution of electrophysiology, play a key role in the study of signal transduction. GIRKs are activated primarily by the G(beta)(gamma) subunits, but a paper by Peleg et al. (2002 [this issue of Neuron]) demonstrates a role for G(alpha) subunits in suppressing basal activity and supports the idea of a macromolecular complex of G protein, GIRK, and perhaps RGS protein.     

Dialogue between RhoA/ROCK and members of the Par complex in cell polarity

Cell polarity is essential for many biological processes and is regulated by conserved protein complexes, including the Par complex, Rho GTPases, and their regulators. In this issue of Developmental Cell, studies by Nakayama et al. and Zhang and Macara examine how interplay between Rho GTPases and the Par complex control polarized cell migration and dendritic spine morphogenesis in alternate ways.     

Can irradiated tumors take NO for an answer?

In a recent issue of Molecular Cell, Li et al. (2007) reported that ionizing radiation stabilizes hypoxia-inducible factor 1alpha (HIF-1alpha) in normoxic tumor tissues through S-nitrosylation by nitric oxide (NO) generated from neighboring activated macrophages.     

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).     

CAT in the HAT: catabolic inhibition by the histone acetyltransferase GCN5

The nuclear hormone receptor coactivator PGC-1alpha is a key regulator of gluconeogenic genes during fasting. In this issue of Cell Metabolism, Puigserver and colleagues (Lerin et al., 2006) report that the histone acetyltransferase GCN5 inhibits gluconeogenesis by acetylating and sequestering PGC-1alpha in nuclear foci.     

Implications of a histone code mimic in epigenetic signaling

In this issue of Molecular Cell, Sampath et al. show a lysine methylase exhibits substrate promiscuity and variability in degree of product methylation (Sampath et al., 2007). Two lysines are found to be automethylated in G9a, and one is H3K9-like and can establish a docking site for HP1 chromodomain.     

Intercalating Arabidopsis leaf cells: a jigsaw puzzle of lobes, necks, ROPs, and RICs

Intercalation of cells is an evolutionarily conserved strategy used for a variety of developmental processes in animals. In this issue of Cell, Fu et al. have uncovered an elaborate Rho GTPase-mediated mechanism by which cytoskeletal-dependent intercalation of Arabidopsis leaf cells is achieved, suggesting that conserved Rho GTPase signaling pathways may similarly regulate tissue morphogenesis in animals and plants.     

Mutational analysis reveals a single binding interface between RhoA and its effector, PRK1

Protein kinase C-related kinases (PRKs) are serine/threonine kinases that are members of the protein kinase C superfamily and can be activated by binding to members of the Rho family of small G proteins via a Rho binding motif known as an HR1 domain. The PRKs contain three tandem HR1 domains at their N-termini. The structure of the HR1a domain from PRK1 in complex with RhoA [Maesaki, R., et al. (1999) Mol. Cell 4, 793-803] identified two potential contact interfaces between the G protein and the HR1a domain. In this work, we have used an alanine scanning mutagenesis approach to identify whether both contact sites are used when the two proteins interact in solution and also whether HR1b, the second HR1 domain from PRK1, plays a role in binding to RhoA. The mutagenesis identified just one contact site as being relevant for binding of RhoA and HR1a in solution, and the HR1b domain was found not to contribute to RhoA binding. The folded state and thermal stability of the HR1a and HR1b domains were also investigated. HR1b was found to be more thermally stable than HR1a, and it is hypothesized that the differences in the biophysical properties of these two domains govern their interaction with small G proteins.     

Fly-let biology and the high protein/low carb diet

In Drosophila, a simple network of nutrient-sensing neuroendocrine cells, analogs of pancreatic islet alpha and beta cells, regulates carbohydrate metabolism. Work presented in this issue of Cell Metabolism (Buch et al., 2008) shows that signals from these cells control expression of a glycogen-specific glucosidase in response to dietary protein and carbohydrate.     

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.     

CUE'd up for Monoubiquitin

The first structures have been obtained for complexes between CUE domains and monoubiquitin, one by NMR (Kang et al., this issue of Cell) and one by X-ray crystallography (Prag et al., this issue of Cell), thus providing insights into ubiquitin recognition by CUE domains. Structural comparisons suggest that different CUE surfaces can interact with ubiquitin, indicating that not all CUE domains are created equal.     

Using isoform-specific inhibitors to target lipid kinases

In this issue of Cell, Knight et al. (2006) present a detailed pharmacological analysis of the PI3 kinase (PI3-K) family using small molecule inhibitors. They conclude that p110alpha, a PI3-K isoform, has a critical role in insulin signaling. In a related Cancer Cell paper, Fan et al. (2006) show that blocking activation of both p110alpha and the kinase mTOR with a small molecule inhibitor limits the growth of gliomas.     

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.     

mTORC2 Caught in a SINful Akt

The target of rapamycin (TOR), a central controller of cell growth, is found in two distinct, highly conserved multiprotein complexes. Three recent papers in Cell (Jacinto et al., 2006), Developmental Cell (shiota et al., 2006; this issue), and Current Biology (Frias et al., 2006) shed light on mTOR complex 2 (mTORC2) composition and in vivo function. An important new finding is that mTORC2 determines Akt/PKB substrate specificity rather than absolute activity.     

Memory, synaptic translation, and...prions?

Two papers from Kausik Si, Eric Kandel, Susan Lindquist, and colleagues set forth a bold new idea for thinking about the mechanisms underlying the generation and maintenance of long-term memories (Si et al., 2003a, 2003b [this issue of Cell]).