Signal Transduction Crosstalk Research Articles

The impact of aging and oxidative stress in metabolic and nervous system disorders: programmed cell death and molecular signal transduction crosstalk.

Life expectancy is increasing throughout the world and coincides with a rise in non-communicable diseases (NCDs), especially for metabolic disease that includes diabetes mellitus (DM) and neurodegenerative disorders. The debilitating effects of metabolic disorders influence the entire body and significantly affect the nervous system impacting greater than one billion people with disability in the peripheral nervous system as well as with cognitive loss, now the seventh leading cause of death worldwide. Metabolic disorders, such as DM, and neurologic disease remain a significant challenge for the treatment and care of individuals since present therapies may limit symptoms but do not halt overall disease progression. These clinical challenges to address the interplay between metabolic and neurodegenerative disorders warrant innovative strategies that can focus upon the underlying mechanisms of aging-related disorders, oxidative stress, cell senescence, and cell death. Programmed cell death pathways that involve autophagy, apoptosis, ferroptosis, and pyroptosis can play a critical role in metabolic and neurodegenerative disorders and oversee processes that include insulin resistance, β-cell function, mitochondrial integrity, reactive oxygen species release, and inflammatory cell activation. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), AMP activated protein kinase (AMPK), and Wnt1 inducible signaling pathway protein 1 (WISP1) are novel targets that can oversee programmed cell death pathways tied to β-nicotinamide adenine dinucleotide (NAD+), nicotinamide, apolipoprotein E (APOE), severe acute respiratory syndrome (SARS-CoV-2) exposure with coronavirus disease 2019 (COVID-19), and trophic factors, such as erythropoietin (EPO). The pathways of programmed cell death, SIRT1, AMPK, and WISP1 offer exciting prospects for maintaining metabolic homeostasis and nervous system function that can be compromised during aging-related disorders and lead to cognitive impairment, but these pathways have dual roles in determining the ultimate fate of cells and organ systems that warrant thoughtful insight into complex autofeedback mechanisms.

α-Mangostin Inhibited M1 Polarization of Macrophages/Monocytes in Antigen-Induced Arthritis Mice by Up-Regulating Silent Information Regulator 1 and Peroxisome Proliferators-Activated Receptor γ Simultaneously.

α-Mangostin (MG) showed the potentials in alleviating experimental arthritis, inhibiting inflammatory polarization of macrophages/monocytes, and regulating peroxisome proliferators-activated receptor γ (PPAR-γ) and silent information regulator 1 (SIRT1) signals. The aim of this study was to analyze the correlations among the above-mentioned properties. Antigen-induced arthritis (AIA) was established in mouse, which was treated with MG in combination with SIRT1/PPAR-γ inhibitors to clarify the role of the two signals in the anti-arthritic actions. Pathological changes were systematically investigated. Phenotypes of cells were investigated by flow cytometry. Expression and co-localization of SIRT1 and PPAR-γ proteins in joint tissues were observed by the immunofluorescence method. Finally, clinical implications from the synchronous up-regulation of SIRT1 and PPAR-γ were validated by experiments in vitro. SIRT1 and PPAR-γ inhibitors (nicotinamide and T0070097) reduced the therapeutic effects of MG on AIA mice, and abrogated MG-induced up-regulation of SIRT1/PPAR-γ and inhibition of M1 polarization in macrophages/monocytes. MG has a good binding affinity to PPAR-γ, and MG promoted the co-expression of SIRT1 and PPAR-γ in joints. Synchronously activating SIRT1 and PPAR-γ was revealed to be necessary by MG to repress inflammatory responses in THP-1 monocytes. MG binds PPAR-γ and excites this signaling to initiate ligand-dependent anti-inflammatory activity. Due to certain unspecified signal transduction crosstalk mechanism, it then promoted SIRT1 expression and further limited inflammatory polarization of macrophages/monocytes in AIA mice.

HER2-driven breast cancer suppression by the JNK signaling pathway

The HER2+ subtype of human breast cancer is associated with the malignant transformation of luminal ductal cells of the mammary epithelium. The sequence analysis of tumor DNA identifies loss of function mutations and deletions of the MAP2K4 and MAP2K7 genes that encode direct activators of the JUN NH2-terminal kinase (JNK). We report that invitro studies of human mammary epithelial cells with CRISPR-induced mutations in the MAPK and MAP2K components of the JNK pathway caused no change in growth in 2D culture, but these mutations promoted epithelial cell proliferation in 3D culture. Analysis of gene expression signatures in 3D culture demonstrated similar changes caused by HER2 activation and JNK pathway loss. The mechanism of signal transduction cross-talk may be mediated, in part, by JNK-suppressed expression of integrin α6β4 that binds HER2 and amplifies HER2 signaling. These data suggest that HER2 activation and JNK pathway loss may synergize to promote breast cancer. To test this hypothesis, we performed invivo studies using a mouse model of HER2+ breast cancer with Cre/loxP-mediated ablation of genes encoding JNK (Mapk8 and Mapk9) and the MAP2K (Map2k4 and Map2k7) that activate JNK in mammary epithelial cells. Kaplan-Meier analysis of tumor development demonstrated that JNK pathway deficiency promotes HER2+-driven breast cancer. Collectively, these data identify JNK pathway genes as potential suppressors for HER2+ breast cancer.

Update on the Roles of Rice MAPK Cascades.

The mitogen-activated protein kinase (MAPK) cascades have been validated playing critical roles in diverse aspects of plant biology, from growth and developmental regulation, biotic and abiotic stress responses, to phytohormone signal transduction or responses. A classical MAPK cascade consists of a MAPK kinase kinase (MAPKKK), a MAPK kinase (MAPKK), and a MAPK. From the 75 MAPKKKs, eight MAPKKs, and 15 MAPKs of rice, a number of them have been functionally deciphered. Here, we update recent advances in knowledge of the roles of rice MAPK cascades, including their components and complicated action modes, their diversified functions controlling rice growth and developmental responses, coordinating resistance to biotic and abiotic stress, and conducting phytohormone signal transduction. Moreover, we summarize several complete MAPK cascades that harbor OsMAPKKK-OsMAPKK-OsMAPK, their interaction with different upstream components and their phosphorylation of diverse downstream substrates to fulfill their multiple roles. Furthermore, we state a comparison of networks of rice MAPK cascades from signal transduction crosstalk to the precise selection of downstream substrates. Additionally, we discuss putative concerns for elucidating the underlying molecular mechanisms and molecular functions of rice MAPK cascades in the future.

Novel functions of the primary cilium in bone disease and cancer.

The primary cilium, a sensory organelle that emanates from the cell surface of most mammalian cell types during growth arrest, has attracted the attention of many researchers over the past decade. Recently, a large number of new findings have assigned novel functions and roles to the primary cilium in signal transduction and related diseases, which has greatly augmented the importance of the cilium in human health and development. Here, we review emerging evidence supporting the primary cilium as a sensory organelle in signal transduction in microgravity, electromagnetic field sensing, chemosensation and tumorigenesis. We also present an overview of signal transduction crosstalk associated with the primary cilium in bone disease and cancer, including primary cilium-related Ca2+ signaling, parathyroid hormone signaling, cAMP signaling, BMP/Smad1/5/8 signaling and Wnt signaling. We anticipate that emerging discoveries about the function of the primary cilium will provide novel insight into the molecular mechanisms of stimulus sensation, signal transduction and pathogenesis.

Biphasic Regulation of Yes-associated Protein (YAP) Cellular Localization, Phosphorylation, and Activity by G Protein-coupled Receptor Agonists in Intestinal Epithelial Cells: A NOVEL ROLE FOR PROTEIN KINASE D (PKD)

We examined the regulation of Yes-associated protein (YAP) localization, phosphorylation, and transcriptional activity in intestinal epithelial cells. Our results show that stimulation of intestinal epithelial IEC-18 cells with the G protein-coupled receptor (GPCR) agonist angiotensin II, a potent mitogen for these cells, induced rapid translocation of YAP from the nucleus to the cytoplasm (within 15 min) and a concomitant increase in YAP phosphorylation at Ser(127) and Ser(397) Angiotensin II elicited YAP phosphorylation and cytoplasmic accumulation in a dose-dependent manner (ED50 = 0.3 nm). Similar YAP responses were provoked by stimulation with vasopressin or serum. Treatment of the cells with the protein kinase D (PKD) family inhibitors CRT0066101 and kb NB 142-70 prevented the increase in YAP phosphorylation on Ser(127) and Ser(397) via Lats2, YAP cytoplasmic accumulation, and increase in the mRNA levels of YAP/TEAD-regulated genes (Ctgf and Areg). Furthermore, siRNA-mediated knockdown of PKD1, PKD2, and PKD3 markedly attenuated YAP nuclear-cytoplasmic shuttling, phosphorylation at Ser(127), and induction of Ctgf and Areg expression in response to GPCR activation. These results identify a novel role for the PKD family in the control of biphasic localization, phosphorylation, and transcriptional activity of YAP in intestinal epithelial cells. In turn, YAP and TAZ are necessary for the stimulation of the proliferative response of intestinal epithelial cells to GPCR agonists that act via PKD. The discovery of interaction between YAP and PKD pathways identifies a novel cross-talk in signal transduction and demonstrates, for the first time, that the PKDs feed into the YAP pathway.

First proteome study of sporadic flowering in bamboo species (Bambusa vulgaris and Dendrocalamus manipureanus) reveal the boom is associated with stress and mobile genetic elements

Bamboo species are the fastest-growing plants having a long vegetative cycle. Abrupt switching from the vegetative phase to the reproductive phase via sporadic flowering boom, occasionally leads to death of bamboo clumps, and threatens the existence of many bamboo species. To apprehend the molecular mechanism driving sporadic flowering, proteome changes in the initial and advanced floral buds of two edible bamboo species (Bambusa vulgaris and Dendrocalamus manipureanus) was dissected by two-dimensional gel electrophoresis (2-DE). A total of 39 differentially expressed peptide spots were identified by matrix-assisted laser desorption ionization time-of-flight/time-of-flight mass spectrometry (MALDI-TOF-TOF/MS). In both B. vulgaris and D. manipureanus, identified proteins were categorized as transposon-related, defence and stress-related, cell cycle related, metabolism related, signal transduction related, and some lacked known putative domains. Proteins such as SEPALLATA3, ubiquitin, histone 3, thaumatin-like protein, putative tethering factor, SF-assemblin, polyubiquitin, mitochondrial carrier-like protein and RPT2-like protein were significantly expressed. Differences in D. manipureanus and B. vulgaris suggested that bamboo species have diverse ‘drivers’ or ‘passengers’ genes that govern natural sporadic flowering boom. This first floral proteomics analysis of bamboos revealed that sporadic boom is a highly energetic process, associated with stress elements, mobile genetic elements and signal transduction cross-talk elements.

Signal Perception and Transduction in Plants

Plants are sessile organisms and are not able to move away from adverse environmental conditions and must response to an array of environmental and developmental cues. They heavily rely on high sensitivity detection and adaptation mechanisms to environmental perturbations. Signal transduction, the means whereby cells construct response to a signal, is a recently defined focus of research in plant biology. Over the past decade our understanding of plant signaling pathways has increased greatly, in part due to the use of molecular genetics and biochemical tools in model plants for example Arabidopsis thaliana and Medicago truncatula. This has assisted us in the identification of components of many signal transduction pathways in diverse physiological systems for example hormonal, developmental and environmental signal transduction pathways and cross-talk between them. During the last 15 years the number of known plant hormones has grown from five to at least ten. Furthermore, many of the proteins involved in plant hormone signaling pathways have been identified, including receptors for many of the major hormones. In addition, recent studies confirm that hormone signaling is integrated at several levels during plant growth and development. In this review paper we have covered recent work in signaling pathway in plants especially how plants sense biotic and abiotic stresses and the potential mechanisms by which different chemical molecules and their downstream signaling components modulates stress tolerance.

Role of signal transduction crosstalk between adenylyl cyclase and MAP kinase in hippocampus-dependent memory

One of the intriguing questions in neurobiology is how long-term memory (LTM) traces are established and maintained in the brain. Memory can be divided into at least two temporally and mechanistically distinct forms. Short-term memory (STM) lasts no longer than several hours, while LTM persists for days or longer. A crucial step in the generation of LTM is consolidation, a process in which STM is converted to LTM. Hippocampus-dependent LTM depends on activation of Ca(2+), Erk/MAP kinase (MAPK), and cAMP signaling pathways, as well as de novo gene expression and translation. One of the transcriptional pathways strongly implicated in LTM is the CREB/CRE (calcium, cAMP response element) transcriptional pathway. Interestingly, this transcriptional pathway may also contribute to other forms of neuroplasticity including adaptive responses to drugs. Evidence discussed in this review indicates that activation of the Erk1/2 MAP Kinase (MAPK)/CRE transcriptional pathway during the formation of hippocampus-dependent memory depends on calmodulin (CaM)-stimulated adenylyl cyclases.

Abstract 236: Characterizing cellular signal transduction cross-talk using in-cell kinase screen

Abstract Cancers are known to be heterogeneous diseases. Tumor cell proliferation and the development of metastatic disease involve the activation of multiple, sometime parallel and often compensatory signal transduction pathways. We have developed a cell-based assay platform that measures specific kinase activity within cells, thus allowing us to conduct pathway-based analyses. This platform can be used for 1) discovering new biomarkers and 2) guiding the design of new therapeutic strategies in personalzed medicine, specifically tailored to the patient's genotype. In the present study, we have used this platform to study the impact of G-protein coupled receptor (GPCR) mediation on IGF-1r (RTK) signal transduction cascades in the presence/absence of oestradiol (ER) using MCF-7 breast cancer cells. The results of these studies indicate that mediating neuroendocrine pathways may be an alternative approach that could enhance the efficacies of specific target therapeutics for the treatment of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 236. doi:1538-7445.AM2012-236

Abstract A13: Overexpression of adipokine receptors and dysregulation of AMPK signaling in normal and hyperplastic endometrium from obese women

Abstract Background: Excess adipose tissue in the obese woman produces inflammatory cytokines, called adipokines, that are thought to regulate proliferation in peripheral tissues such as the endometrium to promote the development of cancer. Epidemiological studies indicate that the adipokines IL-6, leptin, TNFα and adiponectin are dysregulated in the obese woman and in women with endometrial cancer (EC). Activation of the IGF-IR/PI3K/mTOR pathway is an important contributor to the development of endometrial complex atypical hyperplasia (CAH), the precursor to endometrioid-type endometrial cancer. Adipokines act through their receptors to activate pathways that exhibit signal transduction crosstalk with the IGF-IR/PI3K/mTOR pathway that is thought to either promote activation (IL-6, leptin) or inhibit this pathway (TNFα, adiponectin). The goal of these studies was to assess the corresponding adipokine receptors (IL-6Rα, IL6-Rβ, Ob-Rb, AdipoR1, AdipoR2, TNFαR1 and TNFαR2) expression and activation of AMPK and IGF-IR/PI3K/mTOR signaling pathways in normal endometrium from lean and obese women and in endometrial hyperplasia from obese women. Methods: We quantitated adipokine receptor transcript levels of the receptors by qRT-PCR in timed endometrial biopsies obtained from lean women (BMI < 25 kg/m2) and obese women (BMI > 30 kg/m2) that were histologically confirmed to have normal proliferative phase endometrium. These biopsies were compared to biopsies from obese women with endometrial CAH. We assessed functional activation of AMPK and mTOR pathways by immunohistochemistry. Results: There was a significant stepwise increase in the expression of AdipoR1, TNFαR1 and TNFαR2 in normal lean endometrium, normal obese endometrium and obese endometrial CAH. In addition, IL-6Rβ transcripts were significantly increased in obese endometrial CAH as compared to both lean and obese normal endometrium. Phosphorylation of AMPK was increased in obese normal endometrium compared to lean normal endometrium. Surprisingly, in endometrial CAH mTOR signaling was activated and activation of AMPK was lost compared to lean and obese normal endometrium. Conclusions: The stepwise increase in the expression of AdipoR1, TNFαR1 and TNFαR2 in the obese endometrium and endometrial CAH as compared to normal lean endometrium suggests that dysregulation of adipokine receptor expression is an early event and may be predictive of women at risk of developing endometrial CAH and EC. The overexpression of AdipoR1 in obese endometrium may contribute to activation of AMPK. The overexpression of AdipoR1 and activation of AMPK in obese endometrium may be a compensatory mechanism to dampen growth factor signaling through the IGF-IR/PI3K/mTOR pathway. In endometrial CAH there is upregulation of IL-6Rβ which may contribute to activation of mTOR by activating PI3K upstream. Activation of mTOR and loss of AMPK activation may contribute to the abnormal proliferation seen in endometrial CAH. These studies suggest that overexpression of adipokine receptor expression may be an important contributor to the risk of endometrial hyperplasia and cancer in obese women. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A13.

Phosphatidylinositol 3 Kinase/Akt Signal Relay Cooperates with Smad in Bone Morphogenetic Protein-2-Induced Colony Stimulating Factor-1 (CSF-1) Expression and Osteoclast Differentiation

Murine spleen cells produce mature osteoclasts when cocultured with osteoblastic cells. Colony-stimulating factor (CSF)-1 is the growth factor required for differentiating the monocyte-macrophage precursor cells into preosteoclasts. Bone morphogenic protein (BMP) signaling in osteoblasts regulates bone mass in mice, suggesting a role of BMP in osteoclastogenesis along with osteoblast activity. The intracellular signal transduction cross talk regulating the osteoblastic production of CSF-1 as a mechanism of BMP-induced osteoclastogenesis is described in this report. We have recently described the involvement of Smad 1/5 in BMP-2-induced CSF-1 expression and osteoclast formation. In this study, using the pharmacological inhibitors and the adenovirus (Ad) vectors expressing dominant-negative (DN) phosphatidylinositol 3 kinase (PI3K), the PI3K-signaling inhibitor, phosphatase and tensin homolog deleted in chromosome 10 (PTEN) or DN Akt kinase in the in vitro coculture assay, we show an essential role of the lipid kinase cascade in BMP-2-mediated multinucleated osteoclast formation and CSF-1 mRNA expression, transcription, and secretion. Inhibition of PI3K/Akt signaling blocked the binding of Smads 1/5 to the CSF-1 BMP-responsive element present in the CSF-1 promoter, resulting in attenuation of Smad-dependent CSF-1 transcription. Furthermore, PI3K inhibition and DN Akt prevented association of the transcriptional coactivator, CREB (cAMP response element binding protein) binding protein (CBP), with Smads 1/5. Together, these data for the first time demonstrate that PI3K-dependent Akt activation regulates BMP-2-induced CSF-1 expression and provides a mechanism for osteoblastic cell-assisted osteoclast differentiation.

Angiotensin II type-1 receptor regulates RhoA and Rho-kinase/ROCK activation via multiple mechanisms. Focus on “Angiotensin II induces RhoA activation through SHP2-dependent dephosphorylation of the RhoGAP p190A in vascular smooth muscle cells”

angiotensin ii, a crucial regulator of the cardiovascular system, is not only required for physiological functions, such as maintenance of blood pressure and plasma sodium concentration but also is involved in pathophysiological conditions such as hypertension and atherosclerosis (26). Angiotensin II exerts its effect by mainly binding to the angiotensin II type-1 (AT1) receptor. As its seven transmembrane structure suggests, the AT1 receptor couples to several heterotrimeric G proteins including Gq. In addition, the activation of the AT1 receptor leads to increased reactive oxygen species; activation of various protein tyrosine and serine/threonine kinases; and of small G proteins such as Ras, Rac, and RhoA, which may require heterotrimeric G protein-dependent and -independent mechanisms (6, 7, 11, 19).

Signal Transduction Cross Talk Mediated by Jun N-Terminal Kinase-Interacting Protein and Insulin Receptor Substrate Scaffold Protein Complexes

Scaffold proteins have been established as important mediators of signal transduction specificity. The insulin receptor substrate (IRS) proteins represent a critical group of scaffold proteins that are required for signal transduction by the insulin receptor, including the activation of phosphatidylinositol 3 kinase. The c-Jun NH(2)-terminal kinase (JNK)-interacting proteins (JIPs) represent a different group of scaffold molecules that are implicated in the regulation of the JNK. These two signaling pathways are functionally linked because JNK can phosphorylate IRS1 on the negative regulatory site Ser-307. Here we demonstrate the physical association of these signaling pathways using a proteomic approach that identified insulin-regulated complexes of JIPs together with IRS scaffold proteins. Studies using mice with JIP scaffold protein defects confirm that the JIP1 and JIP2 proteins are required for normal glucose homeostasis. Together, these observations demonstrate that JIP proteins can influence insulin-stimulated signal transduction mediated by IRS proteins.

Light modulates the melanophore response to α-MSH in Xenopus laevis: An analysis of the signal transduction crosstalk mechanisms involved

Melanin granule (melanosome) dispersion within Xenopus laevis melanophores is evoked either by light or α-MSH. We have previously demonstrated that the initial biochemical steps of light and α-MSH signaling are distinct, since the increase in cAMP observed in response to α-MSH was not seen after light exposure. cAMP concentrations in response to α-MSH were significantly lower in cells pre-exposed to light as compared to the levels in dark-adapted melanophores. Here we demonstrate the presence of an adenylyl cyclase (AC) in the Xenopus melanophore, similar to the mammalian type IX which is inhibited by Ca 2+–calmodulin-activated phosphatase. This finding supports the hypothesis that the cyclase could be negatively modulated by a light-promoted Ca 2+ increase. In fact, the activity of calcineurin PP2B phosphatase was increased by light, which could result in AC IX inhibition, thus decreasing the response to α-MSH. St-Ht31, a disrupting agent of protein kinase A (PKA)–anchoring kinase A protein (AKAP) complex totally blocked the melanosome dispersing response to α-MSH, but did not impair the photo-response in Xenopus melanophores. Sequence comparison of a melanophore AKAP partial clone with GenBank sequences showed that the anchoring protein was a gravin-like adaptor previously sequenced from Xenopus non-pigmentary tissues. Co-immunoprecipitation of Xenopus AKAP and the catalytic subunit of PKA demonstrated that PKA is associated with AKAP and it is released in the presence of α-MSH. We conclude that in X. laevis melanophores, AKAP12 (gravin-like) contains a site for binding the inactive PKA thus compartmentalizing PKA signaling and also possesses binding sites for PKC. Light diminishes α-MSH-induced increase of cAMP by increasing calcineurin (PP2B) activity, which in turn inhibits adenylyl cyclase type IX, and/or by activating PKC, which phosphorylates the gravin-like molecule, thus destabilizing its binding to the cell membrane.

Cross-regulation of signaling by ITAM-associated receptors

An important function of receptors that signal through immunoreceptor tyrosine-based activation motifs (ITAMs) is to regulate signaling by heterologous receptors. This review describes mechanisms by which ITAM-associated receptors modulate signaling by Toll-like receptors (TLRs), tumor necrosis factor receptor family members and cytokine receptors that use the Jak-STAT signaling pathway, and the biological importance of this signal transduction cross-talk. ITAM-mediated cross-regulation can either augment or dampen signaling by other receptors. Conversely, TLRs and cytokines modulate ITAM-mediated signaling, by means including activation of beta2 integrins that are coupled to the ITAM-containing adaptors DAP12 and FcRgamma. Integration of ITAM signaling into signaling networks through cross-talk with other signal transduction pathways results in tight regulation and fine tuning of cellular responses to various extracellular stimuli and contributes to induction of specific activation and differentiation pathways.

Role of signal transduction cross-talk in memory consolidation

Role of signal transduction cross-talk in memory consolidation

Triple Twist Theory of Rho Inhibition by the Angiotensin II Type 2 Receptor

Although there are some exceptions,1,2 numerous publications support the counterregulatory roles of the angiotensin II type 2 receptor (AT2) against the AT1 receptor functions, such as inhibition of vascular contraction and hypertrophy.3–5 However, it is still very uncertain as to how the AT2 receptor signals interfere with those of the AT1 receptor in the cardiovascular system.5,6 Past findings suggest that the signal transduction of AT1 inhibition by the AT2 receptor may involve multiple distinct mechanisms. Some of these mechanisms appear to be indirect, such as production of nitric oxide through bradykinin opposing the vasoconstrictor actions of the AT1 receptor.3 The direct inhibitory crosstalk of the 2 receptors occurs proximal to the receptor heterodimerization, as well as downstream from the receptors between AT1-activated protein kinases epidermal growth factor receptor kinase and extracellular signal-regulated kinase (ERK)1/2/p42/44 mitogen-activated protein kinase (MAPK), etc and AT2-activated protein phosphatases protein phosphatase 2A, SHP-1, and MAPK phosphatase-1.7,8 The activation of the protein phosphatases by the AT2 receptor may or may not require heterotrimeric G proteins (Gi or Gs) and/or the recently identified AT2 receptor C-terminal tail–interacting proteins.4–6 Given that induction …

Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation

Macrophage phenotype and activation are regulated by cytokines that use the Jak-STAT signaling pathway, microbial recognition receptors that include TLRs, and immunoreceptors that signal via ITAM motifs. The amplitude and qualitative nature of macrophage activation are determined by crosstalk among these signaling pathways. Basal ITAM signaling restrains macrophage responses to TLRs and other activating ligands, whereas strong ITAM signals synergize with the same ligands to activate cells strongly. Similarly, basal ITAM signaling augments IFN signaling and function of receptor activator of NF-kappaB, but extensive ITAM activation inhibits Jak-STAT signaling. Thus, intensity and duration of ITAM signaling determine whether ITAM-coupled receptors augment or attenuate TLR and Jak-STAT responses. IFN-gamma synergizes with TLRs in part by suppressing TLR-induced feedback inhibition, mediated by IL-10 and Stat3, by a mechanism that depends on glycogen synthase kinase (GSK)3 regulation of AP-1 and CREB. IFN-gamma suppresses TLR2 and TLR4 induction/activation of AP-1 by overlapping mechanisms that include regulation of MAPKs, GSK3-dependent suppression of DNA binding, and decreased Fos and Jun protein expression and stability. IFN-gamma suppression of TLR-induced activation of AP-1 and downstream target genes challenges current concepts about the inflammatory role of AP-1 proteins in macrophage activation and is consistent with a role for AP-1 in the generation of noninflammatory osteoclasts. Jak-STAT, TLR, and ITAM pathways are basally active in macrophages and strongly induced during innate responses. Thus, signal transduction crosstalk is regulated in a dynamic manner, which differs under homeostatic and pathologic conditions, and dysregulation of signal transduction crosstalk may contribute to pathogenesis of chronic inflammatory diseases.

Signal Transduction Cross-talk During Colorectal Tumorigenesis

Colorectal carcinoma (CRC) is the second leading cause of cancer-related death in the United States in the general population (men and women combined). Epidemiologic data obtained over the last several decades shows convincing evidence for the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in the reduction of risk of CRC through the inhibition of cycloxygenase (COX). Recent research has also demonstrated that prostaglandin E2 (PGE2), a predominant product of COX, plays a critical role in tumorigenesis of CRCs through its guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs), EP2, and EP4. Molecular analysis of CRC and its precursor lesions have shown that mutation of Adenomatous Polyposis Coli (APC), a gene involved in the wingless type signaling pathway, is an early event during the neoplastic progression in the majority of sporadic CRCs. The fundamental questions are: why is wild type APC so important in adult colorectal tissues in preventing this tumorigenesis, and what are the mechanisms by which NSAIDs prevent colorectal tumorigenesis? We reviewed the recent literature concerning the PGE2-GPCR signaling pathway and the APC-beta-catenin (wingless type) pathway in CRC cells and propose a unifying schema regarding the tumorigenesis of CRC. Colorectal epithelia are continuously exposed to various extracellular agonists (including low levels of PGE2). The binding of these agonists to their corresponding GPCRs leads to formation of activated Galphas, which in turn activates beta-catenin. In normal colorectal epithelia, wild type APC blocks the Galphas-induced activation of beta-catenin, and therefore maintains homeostasis and prevents tumorigenesis. In contrast, in the absence of functional APC, continuous formation of activated Galphas by the binding of various extracellular agonists to their receptors leads to the activation and nuclear accumulation of beta-catenin. This elevated nuclear beta-catenin in turn increases transcription of many genes (COX-2, C-myc, Cyclin D1, vascular endothelial growth factor, T cell factor, etc.) involved in tumorigenesis. Increased transcription of COX-2 also leads to excessive production of PGE2 that in turn forms a stimulatory loop with many biologic functions (proliferation, migration, invasion, angiogenesis, and inhibition of apoptosis), which may result in the development of CRC. Because NSAIDs inhibit COX and decrease the production of PGE2, interruption of the cycle helps prevent colorectal tumorigenesis.