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      Role of cytoskeletal proteins in cerebral cavernous malformation signaling pathways: a proteomic analysis†

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          Abstract

          An in vitro proteomics and systems biology of cerebral cavernous malformation.

          Abstract

          Three genetic mutations were found to cause cerebral cavernous malformation (CCM), a vascular anomaly predisposing affected individuals to hemorrhagic stroke. These CCM proteins function together as a protein complex in the cell. Loss of expression of each CCM gene results in loss of in vitro endothelial tube formation. Label-free differential protein expression analysis using multidimensional liquid chromatography/tandem mass spectrometry (2D-LC-MS/MS) was applied to explore the proteomic profile for loss of each CCM gene expression in mouse endothelial stem cells (MEES) compared to mock shRNA and no shRNA control cell-lines. Differentially expressed proteins were identified ( p < 0.05). 120 proteins were differentially expressed among the cell-lines. Principal component analysis and cluster analysis show the effects of individual knockdown. In all knockdown cell-lines, altered expression of cytoskeletal proteins is the most common. While all CCM mutations result in similar pathology, different CCM mutations have their own distinct pathogenesis in cell signaling.

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          Rapid planetesimal formation in turbulent circumstellar discs

          Anders Johansen, Jeffrey S. Oishi, Mordecai-Mark Mac Low … (2007)
          The initial stages of planet formation in circumstellar gas discs proceed via dust grains that collide and build up larger and larger bodies (Safronov 1969). How this process continues from metre-sized boulders to kilometre-scale planetesimals is a major unsolved problem (Dominik et al. 2007): boulders stick together poorly (Benz 2000), and spiral into the protostar in a few hundred orbits due to a head wind from the slower rotating gas (Weidenschilling 1977). Gravitational collapse of the solid component has been suggested to overcome this barrier (Safronov 1969, Goldreich & Ward 1973, Youdin & Shu 2002). Even low levels of turbulence, however, inhibit sedimentation of solids to a sufficiently dense midplane layer (Weidenschilling & Cuzzi 1993, Dominik et al. 2007), but turbulence must be present to explain observed gas accretion in protostellar discs (Hartmann 1998). Here we report the discovery of efficient gravitational collapse of boulders in locally overdense regions in the midplane. The boulders concentrate initially in transient high pressures in the turbulent gas (Johansen, Klahr, & Henning 2006), and these concentrations are augmented a further order of magnitude by a streaming instability (Youdin & Goodman 2005, Johansen, Henning, & Klahr 2006, Johansen & Youdin 2007) driven by the relative flow of gas and solids. We find that gravitationally bound clusters form with masses comparable to dwarf planets and containing a distribution of boulder sizes. Gravitational collapse happens much faster than radial drift, offering a possible path to planetesimal formation in accreting circumstellar discs.
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            Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization.

            N Yang, O Higuchi, K Ohashi … (1998)
            Rac is a small GTPase of the Rho family that mediates stimulus-induced actin cytoskeletal reorganization to generate lamellipodia. Little is known about the signalling pathways that link Rac activation to changes in actin filament dynamics. Cofilin is known to be a potent regulator of actin filament dynamics, and its ability to bind and depolymerize actin is abolished by phosphorylation of serine residue at 3; however, the kinases responsible for this phosphorylation have not been identified. Here we show that LIM-kinase 1 (LIMK-1), a serine/threonine kinase containing LIM and PDZ domains, phosphorylates cofilin at Ser 3, both in vitro and in vivo. When expressed in cultured cells, LIMK-1 induces actin reorganization and reverses cofilin-induced actin depolymerization. Expression of an inactive form of LIMK-1 suppresses lamellipodium formation induced by Rac or insulin. Furthermore, insulin and an active form of Rac increase the activity of LIMK-1. Taken together, our results indicate that LIMK-1 participates in Rac-mediated actin cytoskeletal reorganization, probably by phosphorylating cofilin.
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              Natural history of the cavernous angioma.

              Jacob T. Robinson, I Awad, Susan Little (1991)
              The incidence and natural history of the cavernous angioma have remained unclear in part because of the difficulty of diagnosing and following this lesion prior to surgical excision. The introduction of magnetic resonance (MR) imaging has improved the sensitivity and specificity of diagnosing and following this vascular malformation. Seventy-six lesions with an MR appearance typical of a presumed cavernous angioma were discovered in 66 patients among 14,035 consecutive MR images performed at the Cleveland Clinic between 1984 and 1989. Follow-up studies in 86% of the cases over a mean period of 26 months provided 143 lesion-years of clinical survey of this condition. The most frequent presenting features were seizure, focal neurological deficit, and headache. While most lesions exhibited evidence of occult bleeding on MR imaging, there was overt hemorrhage in seven of the 57 symptomatic patients and only one overt hemorrhage occurred during the follow-up interval. The annualized bleeding rate was 0.7%. Analysis of the hemorrhage group revealed a significantly greater risk of overt hemorrhage in females. Pathological confirmation of cavernous angioma was obtained in all 14 surgical cases. This information assists in rational therapeutic planning and prognosis in patients with MR images showing lesions suggestive of cavernous angioma.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Biosyst
                Journal ID (iso-abbrev): Mol Biosyst
                Title: Molecular Biosystems
                Publisher: Royal Society of Chemistry
                ISSN (Print): 1742-206X
                ISSN (Electronic): 1742-2051
                Publication date (Print): 3 July 2014
                Publication date (Electronic): 25 April 2014
                Volume: 10
                Issue: 7
                Pages: 1881-1889
                Affiliations
                [a ] David H. Murdock Research Institute , North Carolina Research Campus , Kannapolis , NC 28081 , USA
                [b ] Department of Pharmacology , School of Medicine , University of North Carolina , Chapel Hill , NC 27599 , USA
                [c ] Department of Prosthodontics and the Dental Research Center , School of Dentistry , University of North Carolina , Chapel Hill , NC 27599 , USA
                Author notes

                ‡Department of Prosthodontics, School of Dentistry; and Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA. E-mail: Email: Sompop_Bencharit@ 123456dentistry.unc.edu

                Article
                Publisher ID: c3mb70199a
                DOI: 10.1039/c3mb70199a
                PMC ID: 4043921
                PubMed ID: 24770493
                SO-VID: 253597be-ed4e-4b74-a016-2c1c4384e621
                Copyright © This journal is © The Royal Society of Chemistry 2014
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 24 May 2013
                Date accepted : 16 April 2014
                Categories
                Subject: Chemistry

                Notes

                †Electronic supplementary information (ESI) available. See DOI: 10.1039/c3mb70199a


                ScienceOpen disciplines: Molecular biology
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                ScienceOpen disciplines: Molecular biology

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