Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface.

Members of the epidermal growth factor receptor family (EGFR/ERBB1, ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are key targets for inhibition in cancer therapy. Critical for activation is the formation of an asymmetric dimer by the intracellular kinase domains, in which the carboxy-terminal lobe (C lobe) of one kinase domain induces an active conformation in the other. The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2 (refs 3-5). Crystal structures of complexes between the EGFR kinase domain and a fragment of MIG6 show that a approximately 25-residue epitope (segment 1) from MIG6 binds to the distal surface of the C lobe of the kinase domain. Biochemical and cell-based analyses confirm that this interaction contributes to EGFR inhibition by blocking the formation of the activating dimer interface. A longer MIG6 peptide that is extended C terminal to segment 1 has increased potency as an inhibitor of the activated EGFR kinase domain, while retaining a critical dependence on segment 1. We show that signalling by EGFR molecules that contain constitutively active kinase domains still requires formation of the asymmetric dimer, underscoring the importance of dimer interface blockage in MIG6-mediated inhibition

CC167 How to Use Pastures

Campaign circular 167: How to use Pastures, talks about the growth of desirable grasses and legumes; how to avoid overgrazing and simply make the best pasture

The Tree Inclusion Problem: In Linear Space and Faster

Given two rooted, ordered, and labeled trees $P$ and $T$ the tree inclusion problem is to determine if $P$ can be obtained from $T$ by deleting nodes in $T$. This problem has recently been recognized as an important query primitive in XML databases. Kilpel\"ainen and Mannila [\emph{SIAM J. Comput. 1995}] presented the first polynomial time algorithm using quadratic time and space. Since then several improved results have been obtained for special cases when $P$ and $T$ have a small number of leaves or small depth. However, in the worst case these algorithms still use quadratic time and space. Let $n_S$, $l_S$, and $d_S$ denote the number of nodes, the number of leaves, and the %maximum depth of a tree $S \in \{P, T\}$. In this paper we show that the tree inclusion problem can be solved in space $O(n_T)$ and time: O(\min(l_Pn_T, l_Pl_T\log \log n_T + n_T, \frac{n_Pn_T}{\log n_T} + n_{T}\log n_{T})). This improves or matches the best known time complexities while using only linear space instead of quadratic. This is particularly important in practical applications, such as XML databases, where the space is likely to be a bottleneck.Comment: Minor updates from last tim

A Src-Like Inactive Conformation in the Abl Tyrosine Kinase Domain

The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML). The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 180° with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat CML. The DFG motif is not flipped in crystal structures of inactive forms of the closely related Src kinases, and imatinib does not inhibit c-Src. We present a structure of the kinase domain of Abl, determined in complex with an ATP–peptide conjugate, in which the protein adopts an inactive conformation that resembles closely that of the Src kinases. An interesting aspect of the Src-like inactive structure, suggested by molecular dynamics simulations and additional crystal structures, is the presence of features that might facilitate the flip of the DFG motif by providing room for the phenylalanine to move and by coordinating the aspartate side chain as it leaves the active site. One class of mutations in BCR–Abl that confers resistance to imatinib appears more likely to destabilize the inactive Src-like conformation than the active or imatinib-bound conformations. Our results suggest that interconversion between distinctly different inactive conformations is a characteristic feature of the Abl kinase domain

The Self-Regulated Growth of Supermassive Black Holes

We present a series of simulations of the self--regulated growth of supermassive black holes (SMBHs) in galaxies via three different fueling mechanisms: major mergers, minor mergers, and disk instabilities. The SMBHs in all three scenarios follow the same black hole fundamental plane (BHFP) and correlation with bulge binding energy seen in simulations of major mergers, and observed locally. Furthermore, provided that the total gas supply is significantly larger than the mass of the SMBH, its limiting mass is not influenced by the amount of gas available or the efficiency of black hole growth. This supports the assertion that SMBHs accrete until they reach a critical mass at which feedback is sufficient to unbind the gas locally, terminating the inflow and stalling further growth. At the same time, while minor and major mergers follow the same projected correlations (e.g., the $M_{BH}-\sigma$ and Magorrian relations), SMBHs grown via disk instabilities do not, owing to structural differences between the host bulges. This finding is supported by recent observations of SMBHs in pseudobulges and bulges in barred systems, as compared to those hosted by classical bulges. Taken together, this provides support for the BHFP and binding energy correlations as being more "fundamental" than other proposed correlations in that they reflect the physical mechanism driving the co-evolution of SMBHs and spheroids.Comment: 15 pages, 16 figures, accepted for publication in Ap

The use of propensity scores to assess the generalizability of results from randomized trials

Randomized trials remain the most accepted design for estimating the effects of interventions, but they do not necessarily answer a question of primary interest: Will the program be effective in a target population in which it may be implemented? In other words, are the results generalizable? There has been very little statistical research on how to assess the generalizability, or “external validity,” of randomized trials. We propose the use of propensity-score-based metrics to quantify the similarity of the participants in a randomized trial and a target population. In this setting the propensity score model predicts participation in the randomized trial, given a set of covariates. The resulting propensity scores are used first to quantify the difference between the trial participants and the target population, and then to match, subclassify, or weight the control group outcomes to the population, assessing how well the propensity score-adjusted outcomes track the outcomes actually observed in the population. These metrics can serve as a first step in assessing the generalizability of results from randomized trials to target populations. This paper lays out these ideas, discusses the assumptions underlying the approach, and illustrates the metrics using data on the evaluation of a schoolwide prevention program called Positive Behavioral Interventions and Supports

Csk, a Critical Link of G Protein Signals to Actin Cytoskeletal Reorganization

AbstractHeterotrimeric G proteins can signal to reorganize the actin cytoskeleton, but the mechanism is unclear. Here we report that, in tyrosine kinase Csk-deficient mouse embryonic fibroblast cells, G protein (Gβγ, Gα12, Gα13, and Gαq)-induced, and G protein-coupled receptor-induced, actin stress fiber formation was completely blocked. Reintroduction of Csk into Csk-deficent cells restored the G protein-induced actin stress fiber formation. Chemical rescue experiments with catalytic mutants of Csk demonstrated that the catalytic activity of Csk was required for this process. Furthermore, we uncovered that Gβγ can both translocate Csk to the plasma membrane and directly increase Csk kinase activity. Our genetic and biochemical studies demonstrate that Csk plays a critical role in mediating G protein signals to actin cytoskeletal reorganization