Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations.

Cerebral cavernous malformations (CCMs) are anomalies of the cerebral vasculature. Loss of the CCM proteins CCM1/KRIT1, CCM2, or CCM3/PDCD10 trigger a MAPK-Krüppel-like factor 2 (KLF2) signaling cascade, which induces a pathophysiological pattern of gene expression. The downstream target genes that are activated by KLF2 are mostly unknown.

Novel, non-conventional pathways of necroptosis in the heart and other organs: Molecular mechanisms, regulation and inter-organelle interplay.

Necroptosis, a cell death modality that is defined as a necrosis-like cell death depending on the receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL), has been found to underlie the injury of various organs. Nevertheless, the molecular background of this cell loss seems to also involve, at least under certain circumstances, some novel axes, such as RIPK3-PGAM5-Drp1 (mitochondrial protein phosphatase 5-dynamin-related protein 1), RIPK3-CaMKII (Ca/calmodulin-dependent protein kinase II) and RIPK3-JNK-BNIP3 (c-Jun N-terminal kinase-BCL2 Interacting Protein 3). In addition, endoplasmic reticulum stress and oxidative stress via the higher production of reactive oxygen species produced by the mitochondrial enzymes and the enzymes of the plasma membrane have been implicated in necroptosis, thereby depicting an inter-organelle interplay in the mechanisms of this cell death.

Impaired retinoic acid signaling in cerebral cavernous malformations.

The capillary-venous pathology cerebral cavernous malformation (CCM) is caused by loss of CCM1/Krev interaction trapped protein 1 (KRIT1), CCM2/MGC4607, or CCM3/PDCD10 in some endothelial cells. Mutations of CCM genes within the brain vasculature can lead to recurrent cerebral hemorrhages. Pharmacological treatment options are urgently needed when lesions are located in deeply-seated and in-operable regions of the central nervous system.

β1 integrin monoclonal antibody treatment ameliorates cerebral cavernous malformations.

β1 integrins are important in blood vessel formation and function, finely tuning the adhesion of endothelial cells to each other and to the extracellular matrix. The role of integrins in the vascular disease, cerebral cavernous malformation (CCM) has yet to be explored in vivo. Endothelial loss of the gene KRIT1 leads to brain microvascular defects, resulting in debilitating and often fatal consequences.

CCM2-deficient endothelial cells undergo a ROCK-dependent reprogramming into senescence-associated secretory phenotype.

Cerebral cavernous malformation (CCM) is a cerebrovascular disease in which stacks of dilated haemorrhagic capillaries form focally in the brain. Whether and how defective mechanotransduction, cellular mosaicism and inflammation interplay to sustain the progression of CCM disease is unknown. Here, we reveal that CCM1- and CCM2-silenced endothelial cells expanded in vitro enter into senescence-associated secretory phenotype (SASP) that they use to invade the extracellular matrix and attract surrounding wild-type endothelial and immune cells.

Control of SRC molecular dynamics encodes distinct cytoskeletal responses by specifying signaling pathway usage.

Upon activation by different transmembrane receptors, the same signaling protein can induce distinct cellular responses. A way to decipher the mechanisms of such pleiotropic signaling activity is to directly manipulate the decision-making activity that supports the selection between distinct cellular responses. We developed an optogenetic probe (optoSRC) to control SRC signaling, an example of a pleiotropic signaling node, and we demonstrated its ability to generate different acto-adhesive structures (lamellipodia or invadosomes) upon distinct spatio-temporal control of SRC kinase activity.

CC17 group B Streptococcus exploits integrins for neonatal meningitis development.

Group B Streptococcus (GBS) is the major cause of human neonatal infections. A single clone, designated CC17-GBS, accounts for more than 80% of meningitis cases, the most severe form of the infection. However, the events allowing blood-borne GBS to penetrate the brain remain largely elusive.

Immunofluorescence of Cell-Cell and Cell-Extracellular Matrix Adhesive Defects in In Vitro Endothelial CCM Model: Juxtacrine Role of Mutant Extracellular Matrix on Wild-Type Endothelial Cells.

Endothelial cells lining cerebral cavernous malformations (CCM) present strong adhesive and mechanical defects. Increased cell contractility is a driver to the onset and the expansion of the CCM lesions. 2D in vitro endothelial models have been developed from either endothelial cells isolated from ccm1-3 knock-out mice or CCM1-3-silenced primary endothelial cells.

Interrogating the ccm-3 Gene Network.

Cerebral cavernous malformations (CCMs) are neurovascular lesions caused by mutations in one of three genes (CCM1-3). Loss of CCM3 causes the poorest prognosis, and little is known about how it regulates vascular integrity. The C.

VEGFb, a splice variant of VEGF-A, promotes lung tumor progression and escape from anti-angiogenic therapies through a β1 integrin/VEGFR autocrine loop.

Vascular endothelial growth factor-A (VEGF-A) is highly subjected to alternative pre-mRNA splicing that generates several splice variants. The VEGF and VEGFb families encode splice variants of VEGF-A that differ only at the level of six amino acids in their C-terminal part. The expression level of VEGF splice variants and their function as pro-angiogenic factors during tumor neo-angiogenesis have been well-described.

Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations.

Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system causing strokes and seizures which currently can only be treated through neurosurgery. The disease arises through changes in the regulatory networks of endothelial cells that must be comprehensively understood to develop alternative, non-invasive pharmacological therapies. Here, we present the results of several unbiased small-molecule suppression screens in which we applied a total of 5,268 unique substances to mutant worm, zebrafish, mouse, or human endothelial cells.

The CCM1-CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity.

Endothelial integrity relies on a mechanical crosstalk between intercellular and cell-matrix interactions. This crosstalk is compromised in hemorrhagic vascular lesions of patients carrying loss-of-function mutations in cerebral cavernous malformation (CCM) genes. RhoA/ROCK-dependent cytoskeletal remodeling is central to the disease, as it causes unbalanced cell adhesion towards increased cell-extracellular matrix adhesions and destabilized cell-cell junctions.

ICAP-1 monoubiquitylation coordinates matrix density and rigidity sensing for cell migration through ROCK2-MRCKα balance.

Cell migration is a complex process requiring density and rigidity sensing of the microenvironment to adapt cell migratory speed through focal adhesion and actin cytoskeleton regulation. ICAP-1 (also known as ITGB1BP1), a β1 integrin partner, is essential for ensuring integrin activation cycle and focal adhesion formation. We show that ICAP-1 is monoubiquitylated by Smurf1, preventing ICAP-1 binding to β1 integrin.

Roles of paxillin family members in adhesion and ECM degradation coupling at invadosomes.

Invadosomes are acto-adhesive structures able to both bind the extracellular matrix (ECM) and digest it. Paxillin family members-paxillin, Hic-5, and leupaxin-are implicated in mechanosensing and turnover of adhesion sites, but the contribution of each paxillin family protein to invadosome activities is unclear. We use genetic approaches to show that paxillin and Hic-5 have both redundant and distinctive functions in invadosome formation.

β3 integrin-mediated spreading induced by matrix-bound BMP-2 controls Smad signaling in a stiffness-independent manner.

Understanding how cells integrate multiple signaling pathways to achieve specific cell differentiation is a challenging question in cell biology. We have explored the physiological presentation of BMP-2 by using a biomaterial that harbors tunable mechanical properties to promote localized BMP-2 signaling. We show that matrix-bound BMP-2 is sufficient to induce β3 integrin-dependent C2C12 cell spreading by overriding the soft signal of the biomaterial and impacting actin organization and adhesion site dynamics.

Regulation of β1 integrin-Klf2-mediated angiogenesis by CCM proteins.

Mechanotransduction pathways are activated in response to biophysical stimuli during the development or homeostasis of organs and tissues. In zebrafish, the blood-flow-sensitive transcription factor Klf2a promotes VEGF-dependent angiogenesis. However, the means by which the Klf2a mechanotransduction pathway is regulated to prevent continuous angiogenesis remain unknown.

CCM proteins control endothelial β1 integrin dependent response to shear stress.

Hemodynamic shear stress from blood flow on the endothelium critically regulates vascular function in many physiological and pathological situations. Endothelial cells adapt to shear stress by remodeling their cytoskeletal components and subsequently by changing their shape and orientation. We demonstrate that β1 integrin activation is critically controlled during the mechanoresponse of endothelial cells to shear stress.

Microenvironment, tumor cell plasticity, and cancer.

Purpose Of Review: Much effort has been devoted to determining how cellular and noncellular components of the tumoral niche initiate and promote cancer development. Cancer cells perceive biochemical signals from components of the extracellular matrix (ECM) and sense physical features, such as matrix stiffness and cell confinement. The past decade has seen a better understanding of the biophysics and mechanobiology associated with cancer cells.

The RNA-binding protein Mex3b regulates the spatial organization of the Rap1 pathway.

The four related mammalian MEX-3 RNA-binding proteins are evolutionarily conserved molecules for which the in vivo functions have not yet been fully characterized. Here, we report that male mice deficient for the gene encoding Mex3b are subfertile. Seminiferous tubules of Mex3b-deficient mice are obstructed as a consequence of the disrupted phagocytic capacity of somatic Sertoli cells.

CCM1-ICAP-1 complex controls β1 integrin-dependent endothelial contractility and fibronectin remodeling.

The endothelial CCM complex regulates blood vessel stability and permeability. Loss-of-function mutations in CCM genes are responsible for human cerebral cavernous malformations (CCMs), which are characterized by clusters of hemorrhagic dilated capillaries composed of endothelium lacking mural cells and altered sub-endothelial extracellular matrix (ECM). Association of the CCM1/2 complex with ICAP-1, an inhibitor of β1 integrin, prompted us to investigate whether the CCM complex interferes with integrin signaling.

Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis.

Cerebral cavernous malformations (CCMs) are vascular lesions that can occur sporadically or as a consequence of inherited loss-of-function mutations, predominantly in the genes CCM1 (KRIT1), CCM2 (MGC4607, OSM, Malcavernin), or CCM3 (PDCD10, TFAR15). Inherited, familial CCM is characterized by the development of multiple lesions throughout a patient's life leading to recurrent cerebral hemorrhages. Recently, roles for the CCM proteins in maintaining vascular barrier functions and quiescence have been elucidated, and in this review we summarize the genetics and pathophysiology of this disease and discuss the molecular mechanisms through which CCM proteins may act within blood vessels.