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PDCD10 (CCM3) regulates brain endothelial barrier integrity in cerebral cavernous malformation type 3: role of CCM3-ERK1/2-cortactin cross-talk

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Abstract

Impairment of brain endothelial barrier integrity is critical for cerebral cavernous malformation (CCM) lesion development. The current study investigates changes in tight junction (TJ) complex organization when PDCD10 (CCM3) is mutated/depleted in human brain endothelial cells. Analysis of lesions with CCM3 mutation and brain endothelial cells transfected with CCM3 siRNA (CCM3-knockdown) showed little or no increase in TJ transmembrane and scaffolding proteins mRNA expression, but proteins levels were generally decreased. CCM3-knockdown cells had a redistribution of claudin-5 and occludin from the membrane to the cytosol with no alterations in protein turnover but with diminished protein–protein interactions with ZO-1 and ZO-1 interaction with the actin cytoskeleton. The most profound effect of CCM3 mutation/depletion was on an actin-binding protein, cortactin. CCM3 depletion caused cortactin Ser-phosphorylation, dissociation from ZO-1 and actin, redistribution to the cytosol and degradation. This affected cortical actin ring organization, TJ complex stability and consequently barrier integrity, with constant hyperpermeability to inulin. A potential link between CCM3 depletion and altered cortactin was tonic activation of MAP kinase ERK1/2. ERK1/2 inhibition increased cortactin expression and incorporation into the TJ complex and improved barrier integrity. This study highlights the potential role of CCM3 in regulating TJ complex organization and brain endothelial barrier permeability.

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Acknowledgments

We thank Adrienne Chiu for excellent technical assistance in tissue array analysis. Tissue for this study was provided by Angioma Alliance, St Joseph’s Hospital and Medical Center’s Human Specimen Procurement Service. The confocal microscopy and Laser Capture Microdissection System work was performed in the Microscopy and Image-analysis Laboratory (MIL) at the University of Michigan, Department of Cell & Developmental Biology. Fluorescence microscopy and histology slide scanning was done at Department of pathology Core Flow Cytometry Laboratory and Slide Scanning Services. This work was supported by Public Health Service Grant NS075757 from the National Institute of Neurological Disorders (A.V.A).

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  1. Department of Pathology, University of Michigan, Medical School, 7520A MSRB I, 1150 W Medical Center Dr, Ann Arbor, MI, 48109-5602, USA

    Svetlana M. Stamatovic, Nikola Sladojevic & Anuska V. Andjelkovic

  2. Department of Neurosurgery, University of Michigan, Medical School, R5018 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA

    Richard F. Keep & Anuska V. Andjelkovic

  3. Department of Molecular & Integrative Physiology, University of Michigan, Medical School, R5018 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA

    Richard F. Keep

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  1. Svetlana M. Stamatovic
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Stamatovic, S.M., Sladojevic, N., Keep, R.F. et al. PDCD10 (CCM3) regulates brain endothelial barrier integrity in cerebral cavernous malformation type 3: role of CCM3-ERK1/2-cortactin cross-talk. Acta Neuropathol 130, 731–750 (2015). https://doi.org/10.1007/s00401-015-1479-z

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