Treatment of Donor Rat Hearts Prior to Transplantation with FLIP (FADD-Like Interleukin Beta-Converting Enzyme (FLICE)-Like Inhibitory Protein) in Cardioplegic Solution Decreased Apoptosis at Thirty Minutes Post-transplantation and Decreased Total Tyrosine Phosphorylation Levels.

BACKGROUND Heart transplantation is a therapeutic option for patients with severe coronary artery disease or heart failure. One of the difficulties to overcome is the apoptosis of cardiomyocytes in the donor organ. To prevent apoptosis in the donor organ, we developed a fusion protein containing FLIP (FADD-like interleukin beta-converting enzyme (FLICE)-like inhibitory protein) to inhibit caspase-8.

Identification of novel Ack1-interacting proteins and Ack1 phosphorylated sites in mouse brain by mass spectrometry.

Ack1 (activated Cdc42-associated tyrosine kinase) is a non-receptor tyrosine kinase that is highly expressed in brain. This kinase contains several protein-protein interaction domains and its action is partially regulated by phosphorylation. As a first step to address the neuronal functions of Ack1, here we screened mouse brain samples to identify proteins that interact with this kinase.

New partners and phosphorylation sites of focal adhesion kinase identified by mass spectrometry.

The regulation of focal adhesion kinase (FAK) involves phosphorylation and multiple interactions with other signaling proteins. Some of these pathways are relevant for nervous system functions such as branching, axonal guidance, and plasticity. In this study, we screened mouse brain to identify FAK-interactive proteins and phosphorylatable residues as a first step to address the neuronal functions of this kinase.

The diverse roles and multiple forms of focal adhesion kinase in brain.

Although it was originally characterized as a constituent of focal adhesions in fibroblasts, focal adhesion kinase (FAK) is now considered to be not only a mediator of adhesion processes but also a crucial regulator of guidance and a modulator of gene expression. FAK is the main transducer of the integrin signaling required to stabilize the actin cytoskeleton. However, additional activities have been described over the years.

The CREB/CREM transcription factors negatively regulate early synaptogenesis and spontaneous network activity.

The family of CREB (cAMP response element-binding protein) transcription factors are involved in a variety of biological processes including the development and plasticity of the nervous system. In the maturing and adult brain, CREB genes are required for activity-dependent processes, including synaptogenesis, refinement of connections and long-term potentiation. Here, we use CREB1(Nescre)CREM(-/-) (cAMP-responsive element modulator) mutants to investigate the role of these genes in stimulus-independent patterns of neural activity at early stages.

Regulation of neural migration by the CREB/CREM transcription factors and altered Dab1 levels in CREB/CREM mutants.

The family of CREB transcription factors is involved in a variety of biological processes including the development and plasticity of the nervous system. To gain further insight into the roles of CREB family members in the development of the embryonic brain, we examined the migratory phenotype of CREB1(Nescre)CREM(-/-) mutants. We found that the lack of CREB/CREM genes is accompanied by anatomical defects in specific layers of the olfactory bulb, hippocampus and cerebral cortex.

Bcl-2 overexpression delays caspase-3 activation and rescues cerebellar degeneration in prion-deficient mice that overexpress amino-terminally truncated prion.

Prnp knockout mice that overexpress an amino-truncated form of PrPc (deltaPrP) are ataxic and display cerebellar cell loss and premature death. Studies on the molecular and intracellular events that trigger cell death in these mutants may contribute to elucidate the functions of PrPc and to the design of treatments for prion disease. Here we examined the effects of Bcl-2 overexpression in neurons on the development of the neurological syndrome and cerebellar pathology of deltaPrP.

Nogo-A expression in the human hippocampus in normal aging and in Alzheimer disease.

Myelin-associated proteins are involved in the formation and stabilization of myelin sheaths. In addition, they prevent axon regeneration and plasticity in the adult brain. Recent evidence suggests that the expression of certain myelin-associated proteins (e.

Expression pattern of ACK1 tyrosine kinase during brain development in the mouse.

Ack1 is a non-receptor tyrosine kinase that is highly expressed in the adult central nervous system (CNS). Here, we studied the distribution of Ack1 mRNA throughout the development of mouse CNS. Expression was detected in all areas of the brain but especially high levels were observed in the neocortex, hippocampus, and cerebellum.

Reelin expression and glycosylation patterns are altered in Alzheimer's disease.

Reelin is a glycoprotein that is essential for the correct cytoarchitectonic organization of the developing CNS. Its function in the adult brain is less understood, although it has been proposed that Reelin is involved in signaling pathways linked to neurodegeneration. Here we analyzed Reelin expression in brains and cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients and nondemented controls.

Reelin induces the detachment of postnatal subventricular zone cells and the expression of the Egr-1 through Erk1/2 activation.

Reelin binds to very low-density lipoprotein receptor and apolipoprotein E receptor 2, thereby inducing mDab1 phosphorylation and activation of the phosphatidylinositide 3 kinase (PI3K) pathway. Here we demonstrate that Reelin activates the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) pathway, which leads to the phosphorylation of Erk1/2 proteins. The inhibition of Src family kinases (SFK) blocked Reelin-dependent Erk1/2 activation.

Expression, synaptic localization, and developmental regulation of Ack1/Pyk1, a cytoplasmic tyrosine kinase highly expressed in the developing and adult brain.

Cytosolic tyrosine kinases play a critical role both in neural development and in adult brain function and plasticity. Here we isolated a cDNA with high homology to human Ack1 and mouse Tnk2. This cDNA directs the expression of a 125-kD protein that can be autophosphorylated in tyrosines.

PrP(106-126) activates neuronal intracellular kinases and Egr1 synthesis through activation of NADPH-oxidase independently of PrPc.

Prion diseases are characterised by severe neural lesions linked to the presence of an abnormal protease-resistant isoform of cellular prion protein (PrPc). The peptide PrP(106-126) is widely used as a model of neurotoxicity in prion diseases. Here, we examine in detail the intracellular signalling cascades induced by PrP(106-126) in cortical neurons and the participation of PrPc.

A role of MAP1B in Reelin-dependent neuronal migration.

The signaling cascades governing neuronal migration are believed to link extracellular signals to cytoskeletal components. MAP1B is a neuron-specific microtubule-associated protein implicated in the control of the dynamic stability of microtubules and in the cross-talk between microtubules and actin filaments. Here we show that Reelin can induce mode I MAP1B phosphorylation, both in vivo and in vitro, through gsk3 and cdk5 activation.

MAP1B is required for Netrin 1 signaling in neuronal migration and axonal guidance.

Background: The signaling cascades governing neuronal migration and axonal guidance link extracellular signals to cytoskeletal components. MAP1B is a neuron-specific microtubule-associated protein implicated in the crosstalk between microtubules and actin filaments.

Results: Here we show that Netrin 1 regulates, both in vivo and in vitro, mode I MAP1B phosphorylation, which controls MAP1B activity, in a signaling pathway that depends essentially on the kinases GSK3 and CDK5.

Regulation of Nogo and Nogo receptor during the development of the entorhino-hippocampal pathway and after adult hippocampal lesions.

Axonal regeneration in the adult CNS is limited by the presence of several inhibitory proteins associated with myelin. Nogo-A, a myelin-associated inhibitor, is responsible for axonal outgrowth inhibition in vivo and in vitro. Here we study the onset and maturation of Nogo-A and Nogo receptor in the entorhino-hippocampal formation of developing and adult mice.