Current Signal Transduction Therapy - Volume 4, Issue 2, 2009

Cells respond to extracellular cues through a variety of receptors on the surface. These signals once transduced across the cell membrane, activate protein tyrosine kinases, which through phosphorylation of substrates on key tyrosine residues, are able to control cellular growth, activation and differentiation pathways. Recent data suggest that protein tyrosine kinases are critical in integrating signals from various cellular receptors, including pathogen detection receptors that mediate the host innate immune response. In this article, we have reviewed the roles of tyrosine kinases of the Tec, FAK, Fps, Fer, Syk, Src and TAM-receptor families in toll-like receptor signaling. The shared roles of these tyrosine phosphorylation mediators in host defense, inflammation, autoimmune disease and oncogenesis provides promising avenues for the use of their inhibitors in multiple disorders.

The serotonin (5-HT) transporter (SERT) is implicated in numerous neuropsychiatric disorders including major depression and represents the main target for antidepressants, especially for the selective serotonin reuptake inhibitors (SSRIs). A recently developed SSRI has the particularity to enhance its own reuptake inhibitory activity via the allosteric modulation of SERT. In this review, the SSRI escitalopram, the (S)-enantiomer of the SSRI citalopram, is exemplified in order to illustrate such an allosteric regulation of SERT and to depict putative biochemical mechanisms involving changes in SERT proteins conformations and/or their cellular distribution that could be linked to this antidepressant specificity. Insights into the physiological mechanisms by which SERT is regulated will increase not only our understanding of pathologic processes underlying affective disorders, but can also lead to the development of new strategies to treat these devastating illnesses.

High dose oestrogen therapy was used as a treatment for postmenopausal patients with breast cancer from the 1950s until the introduction of the safer antioestrogen, tamoxifen in the 1970s. The anti-tumour mechanism of high dose oestrogen therapy remained unknown. There was no enthusiasm to study these signal transduction pathways as oestrogen therapy has almost completely been eliminated from the treatment paradigm. Current use of tamoxifen and the aromatase inhibitors seek to create oestrogen deprivation that prevents the growth of oestrogen stimulated oestrogen receptor (ER) positive breast cancer cells. However, acquired resistance to antihormonal therapy does occur, but it is through investigation of laboratory models that a vulnerability of the cancer cell has been discovered and is being investigated to provide new opportunities in therapy with the potential for discovering new cancer-specific apoptotic drugs. Laboratory models of resistance to raloxifene and tamoxifen, the selective oestrogen receptor modulators (SERMs) and aromatase inhibitors demonstrate an evolution of drug resistance so that after many years of oestrogen deprivation, the ER positive cancer cell reconfigures the survival signal transduction pathways so oestrogen now becomes an apoptotic trigger rather than a survival signal. Current efforts are evaluating the mechanisms of oestrogen-induced apoptosis and how this new biology of oestrogen action can be amplified and enhanced, thereby increasing the value of this therapeutic opportunity for the treatment of breast cancer. Several synergistic approaches to therapeutic enhancement are being advanced which involve drug combinations to impair survival signaling with the use of specific agents and to impair bcl-2 that protects the cancer cell from apoptosis. We highlight the historical understanding of oestrogen's role in cell survival and death and specifically illustrate the progress that has been made in the last five years to understand the mechanisms of oestrogen-induced apoptosis. There are opportunities to harness knowledge from this new signal transduction pathway to discover the precise mechanism of this oestrogen-induced apoptotic trigger. Indeed, the new biology of oestrogen action also has significance for understanding the physiology of bone remodeling. Thus, the pathway has a broad appeal in both physiology and cancer research.

Inflammatory signaling networks play critical roles in the interpretation and processing of external and internal challenges encountered by living organisms. Consequently, alterations in various inflammatory processes are linked with almost all human diseases, and provide important clues for potential pharmacological intervention. Macrophages and CD4 T helper cells are central modulators within the inflammatory network. Both cells can adopt distinct phenotypes and activation status depending upon their environments. Consequently, they are critically involved in the progression as well as attenuation of various inflammatory processes. This review will highlight recent progress in our understanding toward the complex activation and differentiation of macrophages and CD4 T helper cells and their involvement in inflammation. Furthermore, we will discuss potential cellular and molecular targets within the inflammatory network for pharmacological intervention of human inflammatory diseases.

17β-Estradiol (E2) controls many aspects of human physiology, including development, reproduction and homeostasis, through regulation of the transcriptional activity of its cognate receptors (ERs). E2 induces profound, rapid effects on the conformation of ERs allowing them to dimerize and to translocate into the nucleus where specific hormone response elements present in DNA are recognized. ER-E2 complex can also function as a cytoplasmic signaling molecule eliciting other changes in cells. Such extra-nuclear or non-genomic signaling pathways are rapid and supposedly independent of transcription. The recent finding that ER also resides at plasma membrane have opened a new spectrum on E2 rapid signaling and raised several new concerns in the field of E2 biology. ERs are now considered as very mobile proteins continuously shuttling between protein targets located within various cellular compartments (e.g., membrane, nucleus). This allows E2 to generate different and synergic signal transduction pathways, which provide plasticity for cell response to E2. Understanding the molecular mechanisms by which ERs transduce E2 signals in target cells will allow to design new pharmacologic therapies aimed at the treatment of a variety of human diseases affecting the cardiovascular, reproductive, skeletal, and the nervous systems as well as the mammary gland.

There is increasing evidence to support the idea that immune modulation is involved in cancer progression. Indeed, the growth in the number of publications describing cancer immunotherapy and how it impacts on cell signaling pathways reinforces this idea. In particular, the forkhead box P3 (Foxp3) transcription factor is an important protagonist in regulatory T cell (Treg) suppression, which has recently been reported to be mediated by the PI3-kinase/AKT/mTOR and TGF-β signaling cascades. This could provide an exciting facet of carcinogenesis, by linking modulation of immuneeffector cells and tumourogenesis of cancer cells. Furthermore, recent findings have indicated a direct role for Foxp3 within tumour cells, and its expression in Tregs has been used as an indicator of poor prognosis in cancer patients. Therapeutic modulation of these systems thus provides an attractive approach to cancer treatment. Additionally, drugcombination strategies utilising agents that target signaling pathways may prove beneficial by simultaneously targeting tumour and immune cells, thereby enhancing native immune response to growing tumours. This article will review the factors involved in Foxp3 expression and highlight the means by which Foxp3-expressing cells could be targeted as a part of cancer immunotherapy.

Protein phosphorylation catalyzed by protein kinases plays critical roles in the regulation of signal-transduction pathways. Deregulated kinase activity is observed in a variety of human diseases, such as cancer, making them targets for the development of molecular therapies. The PI3K/PTEN/AKT/mTOR and RAF/MEK/ERK signaling pathways play fundamental roles in transmitting signals from membrane receptors to downstream targets that regulate apoptosis, cell growth and angiogenesis. Accumulating evidence suggests that both pathways are constitutively activated through multiple genetic and epigenetic mechanisms in a wide variety of human malignancies and play several key functions in cancer development and progression; in that respect, both the PI3K and MAPK pathways function at the bottleneck of signal transduction through protein kinase cascades, thereby constituting attractive therapeutic targets for anti-cancer treatments. These pathways, however, are part of complicated and interwoven regulatory networks and recent evidence suggests that combining inhibitors targeting both the PI3K/PTEN/AKT/mTOR and the RAF/MEK/ERK pathways may avoid tumor escape from single-pathway blockade and ultimately suppress both malignant growth and survival more efficiently. Moreover, both pathways may converge on the regulation of crucial functions, such as neo-angiogenesis, involving not only the cancer cell but also the tumor stroma and the surrounding “normal” compartment. In this review, we describe recent advances in understanding the PI3K and MAPK pathways, in particular the mechanisms by which they regulate tumor growth and angiogenesis, and highlight the potential therapeutic opportunities for targeting these pathways for cancer treatment.

Thyroid hormone (L-3,3,,5-triiodothyronine, T3) is important for the normal function of most tissues, with major actions on O2 consumption and metabolic rate. In the liver, these are due to (i) transcriptional activation of respiratory genes leading to increased reactive O2 species generation in mitochondria and other subcellular sites; and (ii) enhancement in the respiratory burst activity in Kupffer cells (KC), with consequent antioxidant depletion. Under these conditions, the redox upregulation of KC-dependent expression of cytokines (tumor necrosis factor-α, interleukin (IL)-1, IL-6) is achieved, thus triggering the expression of enzymes (inducible nitric oxide synthase, manganese superoxide dismutase), anti-apoptotic proteins (Bcl-2), acute phase proteins (haptoglobin, β-fibrinogen), and hepatocyte proliferation. The above responses (i) represent adaptive mechanisms to re-establish redox homeostasis and promote cell survival; (ii) occur via nuclear factor-κB, signal transducer and activator of transcription-3, and activator protein-1activation; and (iii) afford protection against ischemia-reperfusion liver injury. This strategy represents a novel preconditioning mechanism that has clinical potential either in preventing ischemia-reperfusion injury during liver surgery in man or in liver transplantation using reduced-size grafts from living donors.