The LIM protein Ajuba influences p130Cas localization and Rac1 activity during cell migration

Cell migration requires extension of lamellipodia that are stabilized by formation of adhesive complexes at the leading edge. Both processes are regulated by signaling proteins recruited to nascent adhesive sites that lead to activation of Rho GTPases. The Ajuba/Zyxin family of LIM proteins are components of cellular adhesive complexes. We show that cells from Ajuba null mice are inhibited in their migration, without associated abnormality in adhesion to extracellular matrix proteins, cell spreading, or integrin activation. Lamellipodia production, or function, is defective and there is a selective reduction in the level and tyrosine phosphorylation of FAK, p130Cas, Crk, and Dock180 at nascent focal complexes. In response to migratory cues Rac activation is blunted in Ajuba null cells, as detected biochemically and by FRET analysis. Ajuba associates with the focal adhesion-targeting domain of p130Cas, and rescue experiments suggest that Ajuba acts upstream of p130Cas to localize p130Cas to nascent adhesive sites in migrating cells thereby leading to the activation of Rac

Phospholipase Cγ2 Modulates Integrin Signaling in the Osteoclast by Affecting the Localization and Activation of Src Kinase▿ †

Integrin engagement induces a cascade of signaling pathways that include tyrosine phosphorylation of numerous proteins that lead to modulation of the actin cytoskeleton. Src is a major intracellular mediator of integrin-dependent functions, but the mechanism(s) by which Src is regulated in response to integrin signals is not fully understood. Here, we demonstrate an important role for phospholipase C gamma 2 (PLCγ2) in Src activation in the osteoclast. Through analysis of primary cells from PLCγ2−/− mice, PLCγ2 was found to be an important regulator of αvβ3 integrin-mediated bone osteoclast cell adhesion, migration, and bone resorption. Adhesion-induced PYK2 and Src phosphorylation is decreased in the absence of PLCγ2, and the interaction of Src with β3 integrin and PYK2 is dramatically reduced. Importantly, PLCγ2 was found to be required for proper localization of Src to the sealing actin ring, and this function required both its catalytic activity and adapter domains. Based on these results, we propose that PLCγ2 influences Src activation by mediating the localization of Src to the integrin complex and thereby regulating integrin-mediated functions in the osteoclast

PLCγ2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2

Excessive bone loss in arthritic diseases is mostly due to abnormal activation of the immune system leading to stimulation of osteoclasts. While phospholipase Cγ (PLCγ) isoforms are known modulators of T and B lymphocyte–mediated immune responses, we found that blockade of PLCγ enzymatic activity also blocks early osteoclast development and function. Importantly, targeted deletion of Plcg2 in mice led to an osteopetrotic phenotype. PLCγ2, independent of PLCγ1, was required for receptor activator of NF-κB ligand–induced (RANKL-induced) osteoclastogenesis by differentially regulating nuclear factor of activated T cells c1 (NFATc1), activator protein–1 (AP1), and NF-κB. Specifically, we show that NFATc1 upregulation is dependent on RANKL-mediated phosphorylation of PLCγ2 downstream of Dap12/Fc receptor γ (Dap12/FcRγ) receptors and is blocked by the PLCγ inhibitor U73122. In contrast, activation of JNK and NF-κB was not affected by U73122 or Dap12/FcRγ deletion. Interestingly, we found that in osteoclasts, PLCγ2 formed a complex with the regulatory adapter molecule GAB2, was required for GAB2 phosphorylation, and modulated GAB2 recruitment to RANK. Thus, PLCγ2 mediates RANKL-induced osteoclastogenesis and is a potential candidate for antiresorptive therapy

First measurement of the Z→μ+μ−Z\rightarrow \mu^+ \mu^- angular coefficients in the forward region of pppp collisions at s=13\sqrt{s}=13 TeV

The first study of the angular distribution of $\mu^+ \mu^-$ pairs produced in the forward rapidity region via the Drell-Yan reaction $pp \rightarrow \gamma^{*}/Z +X \rightarrow l^+ l^- + X$ is presented, using data collected with the LHCb detector at a centre-of-mass energy of 13TeV, corresponding to an integrated luminosity of 5.1 $\rm{fb}^{-1}$. The coefficients of the five leading terms in the angular distribution are determined as a function of the dimuon transverse momentum and rapidity. The results are compared to various theoretical predictions of the $Z$-boson production mechanism and can also be used to probe transverse-momentum-dependent parton distributions within the proton

Study of the lineshape of the χc1(3872)\chi_{c1}(3872) state

International audienceA study of the lineshape of the $\chi_{c1}(3872)$ state is made using a data sample corresponding to an integrated luminosity of $3\,$fb$^{-1}$ collected in $pp$ collisions at centre-of-mass energies of 7 and 8\,TeV with the LHCb detector. Candidate $\chi_{c1}(3872)$ and $\psi(2S)$ mesons from b-hadron decays are selected in the $J/\psi \pi^+ \pi^-$ decay mode. Describing the {\mbox{lineshape}} with a Breit--Wigner function, the mass splitting between the $\chi_{c1}(3872)$ and $\psi(2S)$ states, $\Delta m$, and the width of the $\chi_{c1}(3872)$ state, $\Gamma_{\mathrm{BW}}$, are determined to be \begin{eqnarray*} \Delta m & = & 185.598 \pm 0.067 \pm 0.068\, \mathrm{MeV} \,, \\ \Gamma_{\mathrm{BW}} & = & \phantom{00}1.39\phantom{0} \pm 0.24\phantom{0} \pm 0.10\phantom{0} \mathrm{MeV} \,, \end{eqnarray*} where the first uncertainty is statistical and the second systematic. Using a Flatt\'e-inspired model, the mode and full width at half maximum of the lineshape are determined to be \begin{eqnarray*} \mathrm{mode} & = 3871.69^{\,+\,0.00\,+\,0.05}_{\,-\,0.04\,-\,0.13} &\mathrm{MeV} \\ \mathrm{FWHM} & = 0.22^{\,+\,0.07\,+\,0.11}_{\,-\,0.06\,-\,0.13}& \mathrm{MeV} . \end{eqnarray*} An investigation of the analytic structure of the Flatt\'e amplitude reveals a pole structure, which is compatible with a quasi-bound $D^0\bar{D}^{*0}$ state but a quasi-virtual state is still allowed at the level of $2$ standard deviations

Branching Fraction Measurements of the Rare Bs0→ϕμ+μ−B^0_s\rightarrow\phi\mu^+\mu^- and Bs0→f2′(1525)μ+μ−B^0_s\rightarrow f_2^\prime(1525)\mu^+\mu^- Decays

The branching fraction of the rare $B^0_s\rightarrow\phi\mu^+\mu^-$ decay is measured using data collected by the LHCb experiment at center-of-mass energies of 7, 8, and 13 TeV, corresponding to integrated luminosities of 1, 2, and 6 fb$^{-1}$, respectively. The branching fraction is reported in intervals of q$^2$, the square of the dimuon invariant mass. In the q$^2$ region between 1.1 and 6.0 GeV$^2$/c$^4$, the measurement is found to lie 3.6 standard deviations below a standard model prediction based on a combination of light cone sum rule and lattice QCD calculations. In addition, the first observation of the rare $B^0_s\rightarrow f_2^\prime(1525)\mu^+\mu^-$ decay is reported with a statistical significance of 9 standard deviations and its branching fraction is determined