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Activation of Gq protein-coupled receptors triggers the phospholipase C (PLC) pathway, which yields a pair of second messengers: diacylglycerol (DG) and inositol 1,4,5-trisphosphate (IP

Supplementary Figure Legends

Supplementary Figure S1. In vitro PtdIns(3,4,5)P3-phosphatase assay. Supplementary Figure S2. H&E staining of thyroid and lung from a 40-week-old. Supplementary Figure S3. More frequent INPP4B protein reduction in FV-PTCs comparing to non FV-PTCs. Supplementary Figure S4. Representative fluorescent immunohistochemical analyses of sections of human follicular thyroid carcinomas classified in the Low, Medium and High groups of INPP4B and PTEN protein expression. Supplementary Figure S5. Coincident mutations in PTEN and INPP4B genes in thyroid carcinomas and endometrial carcinomas. Supplementary Figure S6. Quantitation of HPLC analyses of phosphoinositides prepared from Pten+/- and Inpp4Bdelta/delta;Pten+/- thyroid glands from mice that were metabolically labeled in vivo with [32H]-phosphorus.

Planar cell polarity (PCP) regulates the orientation of external structures. A core group of proteins that includes Frizzled forms the heart of the PCP regulatory system. Other PCP mechanisms that are independent of the core group likely exist, but their underlying mechanisms are elusive. Here, we show that tissue flow is a mechanism governing core group-independent PCP on the Drosophila notum. Loss of core group function only slightly affects bristle orientation in the adult central notum. This near-normal PCP results from tissue flow-mediated rescue of random bristle orientation during the pupal stage. Manipulation studies suggest that tissue flow can orient bristles in the opposite direction to the flow. This process is independent of the core group and implies that the apical extracellular matrix functions like a “comb” to align bristles. Our results reveal the significance of cooperation between tissue dynamics and extracellular substances in PCP establishment.

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We report electron-atom Compton scattering experiments on the ${\mathrm{H}}_{2}$ and ${\mathrm{D}}_{2}$ molecules. Energy-loss spectra of electrons quasielastically backscattered at an angle of 135\ifmmode^\circ\else\textdegree\fi{} are measured as a function of azimuthal angle at an incident electron energy of 2.0 keV. Momentum distributions of the H and D atoms due to molecular vibration are extracted from the experimental data by using a protocol that we propose here. The results are successfully compared with theoretical ones predicted by the molecular vibrational wave functions. It is shown that electron-atom Compton scattering has a unique ability to provide direct information about intramolecular motion of each atom with different mass numbers.

An apparatus has been developed for electron-atom Compton scattering experiments that can employ a pulsed laser and a picosecond pulsed electron beam in a pump-and-probe scheme. The design and technical details of the apparatus are described. Furthermore, experimental results on the Xe atom in its ground state are presented to illustrate the performance of the pulsed electron gun and the detection and spectrometric capabilities for scattered electrons. The scope of future application is also discussed, involving real-time measurement of intramolecular force acting on each constituent atom with different mass numbers, in a transient, evolving system during a molecular reaction.

We report an (e, 2e) study on interference effects in the spherically-averaged electron momentum density distributions of the five outermost molecular orbitals (MOs) of SF6, which are each constructed from the 2p atomic orbitals (AOs) on the F atoms. The (e, 2e) experiment was performed in the symmetric noncoplanar geometry and at an incident electron energy of 1.2 keV. Interference patterns for each MO have then been obtained by dividing the experimental data by distorted-wave-Born-approximation cross section for an isolated F 2p AO. A detailed analysis of the results shows that the interference patterns afford a rare opportunity to experimentally clarify symmetries of the MOs. Furthermore, it is demonstrated that they provide information about not only the molecular geometry but also the spatial orientation of the constituent AOs even for this relatively complicated molecule.

Inositol polyphosphate 4-phosphatase B (INPP4B) has been identified as a tumor suppressor mutated in human breast, ovary, and prostate cancers. The molecular mechanism underlying INPP4B's tumor-suppressive role is currently unknown. Here, we demonstrate that INPP4B restrains tumor development by dephosphorylating the PtdIns(3,4,5)P3 that accumulates in situations of PTEN deficiency. In vitro, INPP4B directly dephosphorylates PtdIns(3,4,5)P3. In vivo, neither inactivation of Inpp4b (Inpp4bΔ/Δ) nor heterozygous deletion of Pten (Pten+/−) in mice causes thyroid abnormalities, but a combination of these mutations induces malignant thyroid cancers with lung metastases. At the molecular level, simultaneous deletion of Inpp4b and Pten synergistically increases PtdIns(3,4,5)P3 levels and activates AKT downstream signaling proteins in thyroid cells. We propose that the PtdIns(3,4,5)P3 phosphatase activity of INPP4B can function as a “back-up” mechanism when PTEN is deficient, making INPP4B a potential novel therapeutic target for PTEN-deficient or PIK3CA-activated cancers. Significance: Although INPP4B expression is reduced in several types of human cancers, our work on Inpp4B-deficient mice provides the first evidence that INPP4B is a bona fide tumor suppressor whose function is particularly important in situations of PTEN deficiency. Our biochemical data demonstrate that INPP4B directly dephosphorylates PtdIns(3,4,5)P3. Cancer Discov; 5(7); 730–9. ©2015 AACR. See related commentary by Vo and Fruman, p. 697. See related article by Chew et al., p. 740. This article is highlighted in the In This Issue feature, p. 681

Hypertrophic cardiomyopathy (HCM) is a common heart disease with a prevalence of 1 in 500 in the general population. Several mutations in genes encoding cardiac proteins have been found in HCM patients, but these changes do not predict occurrence or prognosis and the molecular mechanisms underlying HCM remain largely elusive. Here we show that cardiac expression of vacuolar protein sorting 34 (Vps34) is reduced in a subset of HCM patients. In a mouse model, muscle-specific loss of Vps34 led to HCM-like manifestations and sudden death. Vps34-deficient hearts exhibited abnormal histopathologies, including myofibrillar disarray and aggregates containing αB-crystallin (CryAB). These features result from a block in the ESCRT-mediated proteolysis that normally degrades K63-polyubiquitinated CryAB. CryAB deposition was also found in myocardial specimens from a subset of HCM patients whose hearts showed decreased Vps34. Our results identify disruption of the previously unknown Vps34-CryAB axis as a potentially novel etiology of HCM.

Summary Background Asymmetric cell division (ACD) is a key process that allows different cell types to be generated at precisely defined times and positions. In Drosophila , neural precursor cells rely heavily on ACD to generate the different cell types in the nervous system. A conserved protein machinery that regulates ACD has been identified in Drosophila , but how this machinery acts to allow the establishment of differential cell fates is not entirely understood. Results To identify additional proteins required for ACD, we have carried out an in vivo live imaging RNAi screen for genes affecting the asymmetric segregation of Numb in Drosophila sensory organ precursor cells. We identify Banderuola (Bnd), an essential regulator of cell polarization, spindle orientation, and asymmetric protein localization in Drosophila neural precursor cells. Genetic and biochemical experiments show that Bnd acts together with the membrane-associated tumor suppressor Discs-large (Dlg) to establish antagonistic cortical domains during ACD. Inhibiting Bnd strongly enhances the dlg phenotype, causing massive brain tumors upon knockdown of both genes. Because the mammalian homologs of Bnd and Dlg are interacting as well, Bnd function might be conserved in vertebrates, and it might also regulate cell polarity in higher organisms. Conclusions Bnd is a novel regulator of ACD in different types of cells. Our data place Bnd at the top of the hierarchy of the factors involved in ACD, suggesting that its main function is to mediate the localization and function of the Dlg tumor suppressor. Bnd has an antioncogenic function that is redundant with Dlg, and the physical interaction between the two proteins is conserved in evolution.