Current
Volume 3, Number 4, 2003
Contents
The FRK/RAK-SHB Signaling Cascade: A
Versatile Signal- Transduction Pathway that Regulates Cell Survival,
Differentiation and
Proliferation Pp.313-324
Cecilia
Anneren , Cecilia K. Lindholm , Vitezslav Kriz and Michael Welsh
Molecular and Genetic Mechanisms of Obesity:
Implications for Future Management Pp.325-340
Yong-Jun
Liu , Sonia Araujo , Robert R. Recker
and Hong-Wen Deng
CD4+ T Cell Responses in the
Immune Control Against Latent Infection by Epstein-Barr Virus Pp.341-347
Casper
Paludan and Christian Munz
Orexigenic/Anorexigenic Signals in Bulimia
Nervosa Pp.349-360
Yoshiyuki
Takimoto , Akio Inui , Hiroaki Kumano
and Tomifusa Kuboki
Stroke: Molecular Mechanisms and Potential
Targets for Treatment
Pp.361-372
Z.
Zheng, J.E. Lee and M.A. Yenari
Regulation of Dendritic Cell Function Through
Toll-like Receptors
Pp.373-385
Tsuneyasu Kaisho, and Shizuo Akira
New Aspects of Integrin-mediated Leukocyte
Adhesion in Inflammation: Regulation by Haemostatic Factors and Bacterial
Products Pp.387-392
Joong-Sup
Rhee , Sentot Santoso , Mathias Herrmann , Angelika Bierhaus , Sandip M. Kanse
, Andreas E. May , Peter P. Nawroth , Robert W. Colman , Klaus T.
Preissner and Triantafyllos
Chavakis
Abstracts
[Back to top] The FRK/RAK-SHB Signaling Cascade: A
Versatile Signal- Transduction Pathway that Regulates Cell Survival,
Differentiation and Proliferation
Cecilia
Anneren , Cecilia K. Lindholm , Vitezslav Kriz and Michael Welsh
Recent experiments
have unravelled novel signal transduction pathways that involve the SRC
homology 2 (SH2) domain adapter protein SHB. SHB is ubiquitously expressed and
contains proline rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine
phosphorylation sites and an SH2 domain and serves a role in generating
signaling complexes in response to tyrosine kinase activation. SHB mediates
certain responses in platelet-derived growth factor (PDGF) receptor-,
fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor
TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion
kinase- (FAK) signaling. Upstream of SHB in some cells lies the SRC-like
FYN-Related Kinase FRK/RAK (also named BSK/IYK or GTK). FRK/RAK and SHB exert
similar effects when overexpressed in rat phaeochromocytoma (PC12) and β-cells,
where they both induce PC12 cell differentiation and β-cell proliferation.
Furthermore, β-cell apoptosis is augmented by these proteins under conditions that
cause β-cell degeneration. The FRK/RAK-SHB responses involve FAK and insulin
receptor substrates (IRS) -1 and -2.
Besides regulating
apoptosis, proliferation and differentiation, SHB is also a component of the T
cell receptor (TCR) signaling response. In Jurkat T cells, SHB links several
signaling components with the TCR and is thus required for IL-2 production. In
endothelial cells, SHB both promotes apoptosis under conditions that are
anti-angiogenic, but is also required for proper mitogenicity, spreading and
tubular morphogenesis. In embryonic stem cells, dominant-negative SHB (R522K)
prevents early cavitation of embryoid bodies and reduces differentiation to
cells expressing albumin, amylase, insulin and glucagon, suggesting a role of
SHB in development.
In summary, SHB is
a versatile signal transduction molecule that produces diverse biological
responses in different cell types under various conditions. SHB operates
downstream of GTK in cells that express this kinase.
[Back to top] Molecular and Genetic Mechanisms of Obesity:
Implications for Future Management
Yong-Jun
Liu , Sonia Araujo , Robert R. Recker
and Hong-Wen Deng
Obesity has become
a worldwide public health problem affecting millions of people. A disruption of
the balance between energy intake and energy expenditure is believed to be the
major cause of obesity. Substantial progress has been made in deciphering the
pathogenesis of energy homeostasis over the past few years. The fact that
obesity is under strong genetic control has been well established. Human
monogenic obesity is rare in large populations, the most common form of obesity
is considered to be a polygenic disorder arising from the interaction of
multiple genetic and environmental factors. Here, we attempt to briefly review
the most recent understanding of molecular mechanisms involved in energy
homeostasis and adipogenesis. We discuss the advantages and disadvantages of
various approaches commonly used in search for susceptibility genes for obesity.
The main results from these genetic studies are summarized, with comments made
on the most striking or representative findings. Finally, the implications of
the recent advances in the understanding of molecular genetic mechanisms of
body weight regulation on prevention and therapeutic intervention of obesity
will be discussed.
[Back to top] CD4+ T Cell Responses in the
Immune Control Against Latent Infection by Epstein-Barr Virus
Casper
Paludan and Christian Munz
The human
ã-herpesvirus Epstein-Barr virus establishes latent, life-long infection in
more than 95% of the human adult population. Despite its growth transforming
capacity, most carriers control EBV associated malignancies efficiently and
remain free of EBV+ tumors. It is commonly accepted that
lymphoblastoid cells, expressing all EBV latent antigens, are targeted by the
immune system and cause tumors only in immune-suppressed individuals. However,
immune control of EBV associated malignancies which express only three or one
EBV latent antigen is less obvious. Recent studies have addressed the pattern
of EBV latent infection in healthy EBV carriers and the identity of EBV derived
target antigens for CD4+ T cells. The results suggest that immune
surveillance also extends to tumors, which have down-regulated most EBV latent
antigens and therefore escape EBV specific immune recognition at least in part.
EBV specific immunity that targets these tumors in healthy EBV carriers seems
to fail specifically during the development of Hodgkin’s disease,
nasopharyngeal carcinoma and Burkitt’s lymphoma. These three EBV+
tumors appear to subdue EBV immunity against the remaining EBV latent antigens
in different ways or profit from the effect of other pathogens on EBV specific
immune responses, when they develop in otherwise immune competent individuals.
While immune control and immune escape of these so-called spontaneously arising
EBV associated malignancies is just beginning to be understood, immune control
of persisting EBV infection can serve as a model for tumor immune surveillance
in general.
[Back to top] Orexigenic/Anorexigenic Signals in Bulimia
Nervosa
Yoshiyuki
Takimoto , Akio Inui , Hiroaki Kumano
and Tomifusa Kuboki
Bulimia nervosa
(BN) and Anorexia Nervosa (AN) are currently classified as eating disorders
(ED). Both disorders are the product of complex interaction between
physiological and psychological and social processes; they are characterized by
abnormal eating behavior. However, patients with BN differ from AN in their
nutritional state and response of treatment with serotonin-selective reuptake
inhibitor (SSRI) as well as frequency of comorbidity of mood and anxiety
disorders. Although biological mechanisms of both BN and AN are largely
unknown, excess of both feeding-stimulatory and feeding inhibitory signaling in
AN have been indicated. This report reviews data that point to the hypothesis
that dysregulation of monoaminergic and new peptidergic circuitry controlling
food intake and energy expenditure play a major role in the eating behavior of
BN.
[Back to top] Stroke: Molecular Mechanisms and Potential
Targets for Treatment
Z. Zheng, J.E. Lee and M.A. Yenari
Significant advances
have been made over the past few years concerning the cellular and molecular
events underlying ischemic cell death. The brain succumbs to ischemic injury as
a result of loss of metabolic stores, excessive intracellular calcium
accumulation, oxidative stress, and potentiation of the inflammatory response.
Neurons can also die via necrotic or apoptotic mechanisms, depending on the
nature and severity of the insult. While it has been widely held that ischemia
is notable for cessation of protein synthesis, brain regions with marginal
reduction in blood supply are especially capable of expressing a variety of
genes, the functions of many of which are only beginning to be understood. Gene
expression is also upregulated upon reperfusion and reoxygenation. As a result,
a number of signaling pathways have been identified and are now known to
contribute to ischemic progression or, in some cases, attempts at self
preservation. This review will focus on the roles of stress genes,
apoptosis-related genes, and inflammation. Knowledge of such molecular events
has fueled interest in developing specific molecular targets with the hope of
someday affecting outcome in clinical stroke.
[Back to top] Regulation of Dendritic Cell Function Through
Toll-like Receptors
Tsuneyasu
Kaisho, and Shizuo Akira
Higher animals
establish host defense by orchestrating innate and adaptive immunity. This is
mediated by professional antigen presenting cells, i.e. dendritic cells (DCs).
DCs can incorporate pathogens, produce a variety of cytokines, maturate, and
present pathogen-derived peptides to T cells, thereby inducing T cell
activation and differentiation. These responses are triggered by microbial
recognition through type I transmembrane proteins, Toll-like receptors (TLRs)
on DCs. TLRs consist of ten members and each TLR is involved in recognizing a
variety of microorganism-derived molecular structures. TLR ligands include cell
wall components, proteins, nucleic acids, and synthetic chemical compounds, all
of which can activate DCs as immune adjuvants.
Each TLR can
activate DCs in a similar, but distinct manner. For example, TLRs can be
divided into subgroups according to their type I interferon (IFN) inducing
ability. TLR2 cannot induce IFN-α or IFN-β, but TLR4 can lead to IFN-β
production. Meanwhile, TLR3, TLR7, and TLR9 can induce both IFN-α and IFN-β.
Recent evidences suggest that cytoplamic adapters for TLRs are especially
crucial for this functional heterogeneity. Clarifying how DC function is regulated
by TLRs should provide us with critical information for manipulating the host
defense against a variety of diseases.
[Back to top] New Aspects of Integrin-mediated Leukocyte
Adhesion in Inflammation: Regulation by Haemostatic Factors and Bacterial
Products
Joong-Sup
Rhee , Sentot Santoso , Mathias Herrmann , Angelika Bierhaus , Sandip M. Kanse
, Andreas E. May , Peter P. Nawroth , Robert W. Colman , Klaus T.
Preissner and Triantafyllos
Chavakis
Leukocyte recruitment
to sites of inflammation, infection or vascular injury is a complex event,
depending on a tightly coordinated sequence of leukocyte-endothelial- and
leukocyte-platelet interactions, which are controlled by the expression and
activation of various adhesion receptors and protease systems. The present
review will focus on novel aspects of the regulation of integrindependent
leukocyte adhesion by haemostatic factors and bacterial products. In
particular, after a short overview of leukocyte recruitment, the review (i)
will focus on the crosstalk between haemostatic factors and adhesion molecules
with respect to leukocyte extravasation based on the paradigms of the urokinase
receptor and high molecular weight kininogen, (ii) will provide information on
novel mechanisms for the regulation of leukocyte recruitment by bacterial
proteins, on the basis of the anti-inflammatory role of Staphylococcus aureus
extracellular adhesive protein and (iii) will draw attention to the junctional
adhesion molecules, a novel family of adhesive receptors that are
counter-receptors for leukocyte integrins and mediate vascular cell
interactions. The better understanding of the interactions between vascular
cells and particularly of integrin-dependent leukocyte adhesion may lead to the
development of novel therapeutical concepts in inflammatory vascular disorders.