The receptor-like kinase SERK3/BAK1 is a central regulator of innate immunity in plants.

In pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI), plant cell surface receptors sense potential microbial pathogens by recognizing elicitors called PAMPs. Although diverse PAMPs trigger PTI through distinct receptors, the resulting intracellular responses overlap extensively. Despite this, a common component(s) linking signal perception with transduction remains unknown.

BAK1 and BKK1 regulate brassinosteroid-dependent growth and brassinosteroid-independent cell-death pathways.

Brassinosteroids (BRs) are phytosteroid hormones controlling various physiological processes critical for normal growth and development. BRs are perceived by a protein complex containing two transmembrane receptor kinases, BRASSINOSTEROID INSENSITIVE 1 (BRI1) and BRI1-ASSOCIATED RECEPTOR KINASE 1 (BAK1) [1-3]. BRI1 null mutants exhibit a dwarfed stature with epinastic leaves, delayed senescence, reduced male fertility, and altered light responses.

BEN1, a gene encoding a dihydroflavonol 4-reductase (DFR)-like protein, regulates the levels of brassinosteroids in Arabidopsis thaliana.

The ben1-1D (bri1-5 enhanced 1-1dominant) mutant was identified via an activation-tagging screen for bri1-5 extragenic modifiers. bri1-5 is a weak mutant allele of the brassinosteroid receptor gene, BRI1. Overexpression of BEN1 greatly enhances the defective phenotypes of bri1-5 plants.

Determinants of growth hormone receptor down-regulation.

GH receptor (GHR) is a cytokine receptor family member that responds to GH by activation of the receptor-associated tyrosine kinase, JAK2 (Janus family of tyrosine kinase 2). We previously showed that JAK2, in addition to being a signal transducer, dramatically increases the half-life of mature GHR, partly by preventing constitutive GHR down-regulation. Herein we explored GHR and JAK2 determinants for both constitutive and GH-induced GHR down-regulation, exploiting the previously characterized GHR- and JAK2-deficient gamma2A reconstitution system.

Combined effect of mutations of the GH1 gene and its proximal promoter region in a child with growth hormone neurosecretory dysfunction (GHND).

Mutational analysis of the growth hormone 1 (GH1) gene and its promoter in a patient with GH neurosecretory dysfunction (GHND) revealed a heterozygous new deletion of one base 7-bp downstream from the 3'-splice site of exon 4 (IVS4'del+7) of the GH1 gene and two new heterozygous mutations at sites -135 and -138 of the GH1 promoter. In addition, two polymorphisms at sites -301 and -308 of the GH1 promoter were observed. All other family members had either the -301/-308 polymorphisms or the IVS4'del+7 mutation, but none had both.

Apoptotic surge of potassium currents is mediated by p38 phosphorylation of Kv2.1.

Kv2.1, the primary delayed rectifying potassium channel in neurons, is extensively regulated by phosphorylation. Previous reports have described Kv2.

In vivo imaging of hepatic growth hormone signaling.

We developed a system to noninvasively and repeatedly image in vivo hepatic GH signaling. GH regulates postnatal growth and metabolism. It affects numerous tissues, but has major effects in liver.

Methylisothiazolinone, a neurotoxic biocide, disrupts the association of SRC family tyrosine kinases with focal adhesion kinase in developing cortical neurons.

Methylisothiazolinone (MIT) is a biocide widely used in industrial and cosmetic products with potential as a neurotoxicant. We previously reported that short acute exposures to relatively high concentrations of MIT (100 microM) lead to widespread and selective neuronal death in vitro. To evaluate the biological properties of chronic exposures to MIT, freshly dissociated rat cortical neurons were continuously exposed to low concentrations (0.

Janus kinase 2 influences growth hormone receptor metalloproteolysis.

GH signals through the GH receptor (GHR), a cytokine receptor superfamily member that couples to the cytoplasmic tyrosine kinase, Janus kinase 2 (JAK2). In addition to its role in signaling, we recently implicated JAK2 in the regulation of cell surface GHR abundance by modulation of GHR trafficking and mature GHR stability. GHR is a target for constitutive and inducible metalloprotease-mediated cleavage that alters surface GHR levels and can modulate GH signaling.

Janus kinase 2 enhances the stability of the mature growth hormone receptor.

The abundance of surface GH receptor (GHR) is an important determinant of cellular GH sensitivity and is regulated at both transcriptional and posttranscriptional levels. In previous studies of GHR-expressing Janus kinase 2 (JAK2)-deficient human fibrosarcoma cells (gamma2A-GHR), we demonstrated that stable transfection with JAK2 resulted in increased steady-state levels of mature GHR (endoH-resistant; relative molecular mass, 115-140 kDa) relative to precursor GHR (endoH-sensitive; relative molecular mass, 100 kDa). We now examine further the effects of JAK2 on GHR trafficking by comparing gamma2A-GHR to gamma2A-GHR cells stably reconstituted with JAK2 (C14 cells).

Identification of 1,2,3,4,5,6-hexabromocyclohexane as a small molecule inhibitor of jak2 tyrosine kinase autophosphorylation [correction of autophophorylation].

The commercially available Jak2 inhibitor, alpha-cyano-3,4-dihydroxy-N-benzylcinnamide (AG490), has been used extensively to study Jak2 kinase function. While alpha-cyano-3,4-dihydroxy-N-benzylcinnamide is a potent Jak2 inhibitor, it can inhibit a number of other kinase signaling pathways as well. To circumvent this problem, we sought to identify novel small molecule inhibitors of Jak2 tyrosine kinase activity.

Growth hormone receptor is a target for presenilin-dependent gamma-secretase cleavage.

Growth hormone receptor (GHR) is a cytokine receptor superfamily member that binds growth hormone (GH) via its extracellular domain and signals via interaction of its cytoplasmic domain with JAK2 and other signaling molecules. GHR is a target for inducible metalloprotease-mediated cleavage in its perimembranous extracellular domain, a process that liberates the extracellular domain as the soluble GH-binding protein and leaves behind a cell-associated GHR remnant protein containing the transmembrane and cytoplasmic domains. GHR metalloproteolysis can be catalyzed by tumor necrosis factor-alpha-converting enzyme (ADAM-17) and is associated with down-modulation of GH signaling.

A conformationally sensitive GHR [growth hormone (GH) receptor] antibody: impact on GH signaling and GHR proteolysis.

The GH receptor (GHR) mediates metabolic and somatogenic actions of GH. Its extracellular domain (ECD; residues 1-246) has two subdomains, each with seven beta strands organized into two antiparallel beta sheets, connected by a short hinge region. Most of the ECD residues involved in GH binding reside in subdomain 1, whereas subdomain 2 harbors a dimerization interface between GHR dimers that alters conformation in response to GH.

Microarray analyses identify JAK2 tyrosine kinase as a key mediator of ligand-independent gene expression.

Mice lacking a functional Janus kinase 2 (JAK2) allele die embryonically, indicating the mandatory role of JAK2 in basic developmental cellular transcription. Currently, however, the downstream target genes of JAK2 are largely unknown. Here, in vitro conditions were created using a cell line lacking JAK2 expression.

Nitrosative stress and potassium channel-mediated neuronal apoptosis: is zinc the link?

Nitrosative stress has been implicated in a large number of neurological disorders. The molecular mechanisms underlying the neuronal injury associated with this stimulus, however, are not clearly understood. Emerging evidence suggests that the liberation of intracellular zinc as well as over-activation of potassium channels may be two important components of nitrosative stress-induced neuronal death.

Diagnosis and treatment of hepatic cholangiocarcinoma: report of 52 cases.

Objective: To summarize the experience in diagnosis and surgical treatment of hepatic cholangiocarcinoma.

Methods: Clinical features, diagnosis, surgical treatment and prognosis of 52 patients with hepatic cholangiocarcinoma treated at our hospital from 1993 to 2001 were retrospectively reviewed.

Results: The patients with hepatic cholangiocarcinoma accounted for 4.

Janus kinase 2 determinants for growth hormone receptor association, surface assembly, and signaling.

GH signaling depends on functional interaction of the GH receptor (GHR) and the cytoplasmic tyrosine kinase, Janus kinase 2 (JAK2), which possesses a C-terminal kinase domain, a catalytically inactive pseudokinase domain just N-terminal to the kinase domain, and an N-terminal half shown by us and others to harbor elements for GHR association. Computational analyses indicate that JAKs contain in their N termini ( approximately 450 residues) divergent FERM domains. FERM domains (or subdomains within them) in JAKS may be important for associations with cytokine receptors.

Reduced proteolysis of rabbit growth hormone (GH) receptor substituted with mouse GH receptor cleavage site.

GH binding protein (GHBP) is a circulating form of the GH receptor (GHR) extracellular domain, which derives by alternative splicing of the GHR gene (in mice and rats) and by metalloprotease-mediated GHR proteolysis with shedding of the extracellular domain as GHBP (in rabbits, humans, and other species). Inducible proteolysis of either mouse (m) or rabbit (rb) GHR is detected in cell culture in response to phorbol ester and other stimuli, yielding a cell-associated GHR remnant (comprised of the cytoplasmic and transmembrane domains and a small portion of the proximal extracellular domain) and down-regulating GH signaling. In this report, we map the mGHR cleavage site by adenoviral overexpression of a membrane-anchored mGHR mutant lacking its cytoplasmic domain and purification and N-terminal sequencing of the phorbol 12-myristate 13-acetate-induced remnant protein.

Antioxidant and pro-oxidant properties of pyrroloquinoline quinone (PQQ): implications for its function in biological systems.

Pyrroloquinoline quinone (PQQ) is a novel redox cofactor recently found in human milk. It has been reported to function as an essential nutrient, antioxidant and redox modulator in cell culture experiments and in animal models of human diseases. As mitochondria are particularly susceptible to oxidative damage we studied the antioxidant properties of PQQ in isolated rat liver mitochondria.

Metalloprotease-mediated GH receptor proteolysis and GHBP shedding. Determination of extracellular domain stem region cleavage site.

Growth hormone-binding protein (GHBP) is complexed to a substantial fraction of circulating GH. In humans, rabbits, and other species, GHBP derives from proteolytic shedding of the GH receptor (GHR) extracellular domain. In cell culture studies, stimuli such as phorbol ester, platelet-derived growth factor, or serum induce GHR proteolysis, which concomitantly yields shed GHBP in cell supernatants and a cell-associated cytoplasmic domain-containing GHR remnant.