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At least 1,783 records · Page 99Linked to original sources
PubMed2002

Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes.

CD40/CD40L interaction is essential for multiple biological events in T dependent humoral immune responses, including B cell survival and proliferation, germinal center and memory B cell formation, and antibody isotype switching and affinity maturation. By using high-density microarrays, we examined gene expression in primary mouse B lymphocytes after multiple time points of CD40L stimulation. In addition to genes involved in cell survival and growth, which are also induced by other mitogens such as lipopolysaccharide, CD40L specifically activated genes involved in germinal center formation and T cell costimulatory molecules that facilitate T dependent humoral immunity. Next, by examining the roles of individual CD40-activated signal transduction pathways, we dissected the overall CD40-mediated response into genes independently regulated by the individual pathways or collectively by all pathways. We also found that gene down-regulation is a significant part of the overall response and that the p38 pathway plays an important role in this process, whereas the NF-kappa B pathway is important for the up-regulation of primary response genes. Our finding of overlapping independent control of gene expression modules by different pathways suggests, in principle, that distinct biological behaviors that depend on distinct gene expression subsets can be manipulated by targeting specific signaling pathways.

Animals↗
PubMed2004

Mechanical switching and coupling between two dissociation pathways in a P-selectin adhesion bond.

Many biomolecular bonds exhibit a mechanical strength that increases in proportion to the logarithm of the rate of force application. Consistent with exponential decrease in bond lifetime under rising force, this kinetically limited failure reflects dissociation along a single thermodynamic pathway impeded by a sharp free energy barrier. Using a sensitive force probe to test the leukocyte adhesion bond P-selectin glycoprotein ligand 1 (PSGL-1)-P-selectin, we observed a linear increase of bond strength with each 10-fold increase in the rate of force application from 300 to 30,000 pN/sec, implying a single pathway for failure. However, the strength and lifetime of PSGL-1-P-selectin bonds dropped anomalously when loaded below 300 pN/sec, demonstrating unexpectedly faster dissociation and a possible second pathway for failure. Remarkably, if first loaded by a "jump" in force to 20-30 pN, the bonds became strong when subjected to a force ramp as slow as 30 pN/sec and exhibited the same single-pathway kinetics under all force rates. Applied in this way, a new "jump/ramp" mode of force spectroscopy was used to show that the PSGL-1-P-selectin bond behaves as a mechanochemical switch where force history selects between two dissociation pathways with markedly different properties. Furthermore, replacing PSGL-1 by variants of its 19-aa N terminus and by the crucial tetrasaccharide sialyl LewisX produces dramatic changes in the failure kinetics, suggesting a structural basis for the two pathways. The two-pathway switch seems to provide a mechanism for the "catch bond" response observed recently with PSGL-1-P-selectin bonds subjected to small-constant forces.

Gangliosides↗
PubMed2001

Two recombination-dependent DNA replication pathways of bacteriophage T4, and their roles in mutagenesis and horizontal gene transfer.

Two major pathways of recombination-dependent DNA replication, "join-copy" and "join-cut-copy," can be distinguished in phage T4: join-copy requires only early and middle genes, but two late proteins, endonuclease VII and terminase, are uniquely important in the join-cut-copy pathway. In wild-type T4, timing of these pathways is integrated with the developmental program and related to transcription and packaging of DNA. In primase mutants, which are defective in origin-dependent lagging-strand DNA synthesis, the late pathway can bypass the lack of primers for lagging-strand DNA synthesis. The exquisitely regulated synthesis of endo VII, and of two proteins from its gene, explains the delay of recombination-dependent DNA replication in primase (as well as topoisomerase) mutants, and the temperature-dependence of the delay. Other proteins (e.g., the single-stranded DNA binding protein and the products of genes 46 and 47) are important in all recombination pathways, but they interact differently with other proteins in different pathways. These homologous recombination pathways contribute to evolution because they facilitate acquisition of any foreign DNA with limited sequence homology during horizontal gene transfer, without requiring transposition or site-specific recombination functions. Partial heteroduplex repair can generate what appears to be multiple mutations from a single recombinational intermediate. The resulting sequence divergence generates barriers to formation of viable recombinants. The multiple sequence changes can also lead to erroneous estimates in phylogenetic analyses.

Amino Acid Sequence↗
PubMed2000

v-Crk activates the phosphoinositide 3-kinase/AKT pathway in transformation.

v-Crk induces cellular tyrosine phosphorylation and transformation of chicken embryo fibroblasts (CEF). We studied the molecular mechanism of the v-Crk-induced transformation. Experiments with Src homology (SH)2 and SH3 domain mutants revealed that the induction of tyrosine phosphorylation of cellular proteins requires only the SH2 domain, but both the SH2 and SH3 domains are required for complete transformation. Analysis of three well defined signaling pathways, the mitogen-activated protein kinase (MAPK) pathway, the Jun N-terminal kinase (JNK) pathway, and the phosphoinositide 3-kinase (PI3K)/AKT pathway, demonstrated that only the PI3K/AKT pathway is constitutively activated in v-Crk-transformed CEF. Both the SH2 and SH3 domains are required for this activation of the PI3K/AKT pathway in CEF. We also found that the colony formation of CEF is strongly induced by a constitutively active PI3K mutant, and that a PI3K inhibitor, LY294002, suppresses the v-Crk-induced transformation. These results strongly suggest that constitutive activation of the PI3K/AKT pathway plays an essential role in v-Crk-induced transformation of CEF.

Animals↗
PubMed2003

Identification of T cell-signaling pathways that stimulate latent HIV in primary cells.

Eradication of HIV infection depends on the elimination of a small, but stable population of latently infected T cells. After the discontinuation of therapy, activation of latent virus can rekindle infection. To purge this reservoir, it is necessary to define cellular signaling pathways that lead to activation of latent HIV. We used the SCID-hu (Thy/Liv) mouse model of HIV latency to analyze a broad array of T cell-signaling pathways and show in primary, quiescent cells that viral induction depends on the activation of two primary intracellular signaling pathways, protein kinase C or nuclear factor of activated T cells (NF-AT). In contrast, inhibition or activation of other important T cell stimulatory pathways (such as mitogen-activated protein kinase, calcium flux, or histone deacetylation) do not significantly induce virus expression. We found that the activation of NF-kappaB is critical to viral reactivation; however, all pathways that stimulate NF-kappaBdonot reactivate latent virus. Our studies further show that inhibition of NF-kappaB does not prevent activation of HIV by NF-AT, indicating that these pathways can function independently to activate the HIV LTR. Thus, we define several molecular pathways that trigger HIV reactivation from latency and provide evidence that latent HIV infection is maintained by the functional lack of particular transcription factors in quiescent cells.

Animals↗
PubMed1989

Coordinated regulation of intracellular K+ in the proximal tubule: Ba2+ blockade down-regulates the Na+,K+-ATPase and up-regulates two K+ permeability pathways.

To avoid large changes in cell K+ content and volume during variations in Na+,K+-ATPase activity, Na+-transporting epithelia must adjust the rate of K+ exit through passive permeability pathways. Recent studies have shown that a variety of passive K+ transport mechanisms may coexist within a cell and may be functionally linked to the activity of the Na+,K+-ATPase. In this study, we have identified three distinct pathways for passive K+ transport that act in concert with the Na+,K+-ATPase to maintain intracellular K+ homeostasis in the proximal tubule. Under control conditions, the total K+ leak of the tubules consisted of discrete Ba2+-sensitive (approximately 65%), quinine-sensitive (approximately 20%), and furosemide-sensitive (approximately 10%) pathways. Following inhibition of the principal K+ leak pathway with Ba2+, the tubules adaptively restored cell K+ content to normal levels. This recovery of cell K+ content was inhibited, in an additive manner, by quinine and furosemide. Following adaptation to Ba2+, the tubules exhibited a 30% reduction in Na+-K+ pump rate coupled with an increase in K+ leak by means of the quinine-sensitive (approximately 70%) and furosemide-sensitive (approximately 280%) pathways. Thus, the proximal tubule maintains intracellular K+ homeostasis by the coordinated modulation of multiple K+ transport pathways. Furthermore, these results suggest that, like Ba2+, other inhibitors of K+ conductance will cause compensatory changes in both the Na+-K+ pump and alternative pathways for passive K+ transport.

Animals↗
PubMed1998

MMS2, encoding a ubiquitin-conjugating-enzyme-like protein, is a member of the yeast error-free postreplication repair pathway.

Among the three Saccharomyces cerevisiae DNA repair epistasis groups, the RAD6 group is the most complicated and least characterized, primarily because it consists of two separate repair pathways: an error-free postreplication repair pathway, and a mutagenesis pathway. The rad6 and rad18 mutants are defective in both pathways, and the rev3 mutant affects only the mutagenesis pathway, but a yeast gene that is involved only in error-free postreplication repair has not been reported. We cloned the MMS2 gene from a yeast genomic library by functional complementation of the mms2-1 mutant [Prakash, L. & Prakash, S. (1977) Genetics 86, 33-55]. MMS2 encodes a 137-amino acid, 15.2-kDa protein with significant sequence homology to a conserved family of ubiquitin-conjugating (Ubc) proteins. However, Mms2 does not appear to possess Ubc activity. Genetic analyses indicate that the mms2 mutation is hypostatic to rad6 and rad18 but is synergistic with the rev3 mutation, and the mms2 mutant is proficient in UV-induced mutagenesis. These phenotypes are reminiscent of a pol30-46 mutant known to be impaired in postreplication repair. The mms2 mutant also displayed a REV3-dependent mutator phenotype, strongly suggesting that the MMS2 gene functions in the error-free postreplication repair pathway, parallel to the REV3 mutagenesis pathway. Furthermore, with respect to UV sensitivity, mms2 was found to be hypostatic to the rad6Delta1-9 mutation, which results in the absence of the first nine amino acids of Rad6. On the basis of these collective results, we propose that the mms2 null mutation and two other allele-specific mutations, rad6Delta1-9 and pol30-46, define the error-free mode of DNA postreplication repair, and that these mutations may enhance both spontaneous and DNA damage-induced mutagenesis.

Alleles↗
PubMed1998

The underlying pathway structure of biochemical reaction networks.

Bioinformatics is yielding extensive, and in some cases complete, genetic and biochemical information about individual cell types and cellular processes, providing the composition of living cells and the molecular structure of its components. These components together perform integrated cellular functions that now need to be analyzed. In particular, the functional definition of biochemical pathways and their role in the context of the whole cell is lacking. In this study, we show how the mass balance constraints that govern the function of biochemical reaction networks lead to the translation of this problem into the realm of linear algebra. The functional capabilities of biochemical reaction networks, and thus the choices that cells can make, are reflected in the null space of their stoichiometric matrix. The null space is spanned by a finite number of basis vectors. We present an algorithm for the synthesis of a set of basis vectors for spanning the null space of the stoichiometric matrix, in which these basis vectors represent the underlying biochemical pathways that are fundamental to the corresponding biochemical reaction network. In other words, all possible flux distributions achievable by a defined set of biochemical reactions are represented by a linear combination of these basis pathways. These basis pathways thus represent the underlying pathway structure of the defined biochemical reaction network. This development is significant from a fundamental and conceptual standpoint because it yields a holistic definition of biochemical pathways in contrast to definitions that have arisen from the historical development of our knowledge about biochemical processes. Additionally, this new conceptual framework will be important in defining, characterizing, and studying biochemical pathways from the rapidly growing information on cellular function.

Biochemistry↗
PubMed1999

T cell antigen receptor-mediated activation of the Ras/mitogen-activated protein kinase pathway controls interleukin 4 receptor function and type-2 helper T cell differentiation.

The central role of type-2 helper T (Th2) cells in the development of allergic responses and immune responses against helminthic parasites is well documented. The differentiation of Th2 cells from naive T cells requires both the recognition of antigen by T cell antigen receptors (TCR) and the activation of downstream signal-transduction molecules of the interleukin 4 receptor (IL-4R) pathway, including Jak1, Jak3, and STAT6. Little is known, however, about how these two distinct pathways cooperate with each other to induce Th2 cells. Here, we use a T cell-specific H-Ras-dominant-negative transgenic mouse to show that TCR-mediated activation of the Ras/mitogen-activated protein kinase pathway alters IL-4R function and is required for Th2 cell differentiation. The enhancement of IL-4R signaling seems to be a consequence of both direct "crosstalk" with the TCR signaling pathway and increased protein expression of downstream signaling molecules of the IL-4R pathway. Therefore, successful Th2 differentiation depends on the effectiveness of the TCR-mediated activation of the Ras/mitogen-activated protein kinase pathway in modifying the IL-4R-mediated signaling pathway.

Animals↗
PubMed1996

Role of the low density lipoprotein (LDL) receptor pathway in the metabolism of chylomicron remnants. A quantitative study in knockout mice lacking the LDL receptor, apolipoprotein E, or both.

Two receptor pathways are thought to mediate the hepatic clearance of chylomicron remnants, (i) the low density lipoprotein receptor (LDLR) pathway and (ii) non-LDLR pathway. The current study was undertaken to quantitatively assess the contribution of each receptor pathway to hepatic catabolism of chylomicron remnants, by using mice that are deficient in apolipoprotein E (apoE) (apoE(-/-)), the LDLR (LDLR(-/-)), and both (apoE(-/-);LDLR(-/-)). Vitamin A fat tolerance tests showed that the area under the curves of the plasma excursions of retinyl ester in the LDLR(-/-), apoE(-/-), and apoE(-/-);LDLR(-/-) mice were 4, 12, and 12 times larger than those in wild-type mice. The retinyl ester accumulated in the plasma of the LDLR(-/-) mice was distributed in larger subfractions of triglyceride-rich lipoproteins, chylomicrons through very low density lipoprotein-C. These results indicate that the LDLR constitutes the major pathway for the clearance of retinyl ester. In support of this, agarose gel electrophoresis revealed that an oral fat load resulted in retention of chylomicrons in the LDLR(-/-) mice, which was not seen in wild-type mice. The observation that the apoE(-/-) mice showed larger retinyl ester excursion than LDLR(-/-) mice indicates that an apoE-dependent non-LDLR pathway is involved in the rest of the clearance of the retinyl ester. Together, we conclude that the LDLR pathway plays a significant role in the chylomicron remnant metabolism in mice fed a normal chow.

Animals↗
PubMed1998

p38 mitogen-activated protein kinase-dependent and -independent intracellular signal transduction pathways leading to apoptosis in human neutrophils.

Human neutrophils undergo apoptosis spontaneously when cultured in vitro; however, the signal transduction pathways involved remain largely unknown. In some cell types, c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase (MAPK) have been implicated in the pathways leading to stress-induced apoptosis. In this study, we begin to define two pathways leading to apoptosis in the neutrophil induced either by stress stimuli (UV, hyperosmolarity, sphingosine) or by anti-Fas antibody or overnight culture in vitro (spontaneous apoptosis). Apoptosis induced by stress stimuli activated p38 MAPK, and apoptosis was inhibited by the specific p38 MAPK inhibitor, 6-(4-Fluorophenyl)-2.3-dihydro-5-(4-puridinyl)imidazo(2, 1-beta)thiazole dihydrochloride. Furthermore, differentiation of HL-60 cells toward the neutrophil phenotype resulted in a loss in c-Jun NH2-terminal kinase activation with concomitant acquisition of formylmethionylleucylphenylalanine-stimulatable and stress-inducible p38 MAPK activity as well as apoptosis blockade by the p38 MAPK inhibitor. In contrast, anti-Fas-induced or spontaneous apoptosis occurred independent of p38 MAPK activation and was not blocked by the inhibitor. Both pathways appear to utilize member(s) of the caspase family, since pretreatment with either Val-Ala-Asp-fluoromethyl ketone or Asp-Glu-Val-Asp-fluoromethyl ketone inhibited apoptosis induced by each of the stimuli. We propose the presence of at least two pathways leading to apoptosis in human neutrophils, a stress-activated pathway that is dependent on p38 MAPK activation and an anti-FAS/spontaneous pathway that is p38 MAPK-independent.

Apoptosis↗
PubMed1998

The GABP-responsive element of the interleukin-2 enhancer is regulated by JNK/SAPK-activating pathways in T lymphocytes.

T cell activation leads via multiple intracellular signaling pathways to rapid induction of interleukin-2 (IL-2) expression, which can be mimicked by costimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA) and ionomycin. We have identified a distal IL-2 enhancer regulated by the Raf-MEK-ERK signaling pathway, which can be induced by TPA/ionomycin treatment. It contains a dyad symmetry element (DSE) controlled by the Ets-like transcription factor GA-binding protein (GABP), a target of activated ERK. TPA/ionomycin treatment of T cells stimulates both mitogen-activated ERK, as well as the stress-activated mitogen-activated protein kinase family members JNK/SAPK and p38. In this study, we investigated the contribution of the stress-activated pathways to the induction of the distal IL-2 enhancer. We show that JNK- but not p38-activating pathways regulate the DSE activity. Furthermore, the JNK/SAPK signaling pathway cooperates with the Raf-MEK-ERK cascade in TPA/ionomycin-induced DSE activity. In T cells, overexpression of SPRK/MLK3, an activator of JNK/SAPK, strongly induces DSE-dependent transcription and dominant negative kinases of SEK and SAPK impair TPA/ionomycin-induced DSE activity. Blocking both ERK and JNK/SAPK pathways abolishes the DSE induction. The inducibility of the DSE is strongly dependent on the Ets-core motifs, which are bound by GABP. Both subunits of GABP are phosphorylated upon JNK activation in vivo and three different isoforms of JNK/SAPK, but not p38, in vitro. Our data suggest that GABP is targeted by signaling events from both ERK and JNK/SAPK pathways. GABP therefore is a candidate for signal integration and regulation of IL-2 transcription in T lymphocytes.

3T3 Cells↗
PubMed1998

A signal peptide that directs non-Sec transport in bacteria also directs efficient and exclusive transport on the thylakoid Delta pH pathway.

Signal peptides that specifically direct precursor proteins to the thylakoid Delta pH pathway possess an N domain RR motif. Signal peptides that direct transport of bacterial proteins across a non-Sec export pathway possess an N domain RRXFLK consensus motif. Recent genetic studies suggest an evolutionary link between these two protein translocation pathways. To further explore this relationship, we examined the thylakoid targeting capability of the signal peptide for Escherichia coli hydrogenase 1 small subunit (HyaA) by linking it to plastocyanin and assaying the chimeric protein in an in vitro thylakoid transport assay. The chimeric precursor was transported across thylakoids with high efficiency. Transport was characteristic of the Delta pH but not the Sec pathway, i.e. it was eliminated by ionophores that dissipate the DeltapH but occurred in the absence of stromal extract or ATP. This result was confirmed by competition with chemical quantities of a Delta pH pathway precursor. This indicates that the HyaA signal peptide has the necessary elements for efficient and exclusive targeting to the Delta pH pathway and further supports the notion that the alternate targeting pathways in prokaryotes and plant thylakoids are analogous.

Adenosine Triphosphatases↗
PubMed1998

Phosphoinositide 3-kinase induces scattering and tubulogenesis in epithelial cells through a novel pathway.

Hepatocyte growth factor/scatter factor (HGF/SF) treatment of the Madin-Darby canine kidney epithelial cell line causes scattering of cells grown in monolayer culture and the formation of branching tubules by cells grown in collagen gels. HGF/SF causes prolonged activation of both the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase 2 (ERK2) and the phosphoinositide 3-OH kinase (PI 3-kinase) target protein kinase B (PKB)/Akt; inhibition of either the MAP kinase pathway by the MAP kinase/ERK kinase inhibitor PD98059 or the PI 3-kinase pathway by LY294002 blocks HGF/SF induction of scattering, although in morphologically distinct ways. Expression of constitutively activated PI 3-kinase, Ras, or R-Ras will cause scattering, but activated Raf will not, indicating that activation of the MAP kinase pathway is not sufficient for this response. Downstream of PI 3-kinase, activated PKB/Akt and Rac are both unable to induce scattering, implicating a novel pathway. Scattering induced by Ras or PI 3-kinase is sensitive to PD98059, as well as to LY294002, suggesting that basal MAP kinase activity is required, but not sufficient, for the scattering response. Induction of MDCK cell tubulogenesis in collagen gels by HGF/SF is inhibited by PD98059; expression of activated Ras and Raf causes disorganized growth in this system, but activated PI 3-kinase or R-Ras causes branching tubule formation similar to that seen with HGF/SF treatment. These data indicate that multiple signaling pathways acting downstream of Met and Ras are needed for these morphological effects; scattering is induced primarily by the PI 3-kinase pathway, which acts through effectors other than PKB/Akt or Rac and requires at least basal MAP kinase function. Elevated PI 3-kinase activity induces tubulogenesis, but total inhibition and excess activation of the MAP kinase pathway both oppose this effect.

Animals↗
PubMed1999

Evidence for a 3'-5' decay pathway for c-myc mRNA in mammalian cells.

Many mRNAs in mammalian cells decay via a sequential pathway involving rapid conversion of polyadenylated molecules to a poly(A)-deficient state followed by rapid degradation of the poly(A)-deficient molecules. However, the rapidity of this latter step(s) has precluded further analyses of the decay pathways involved. Decay intermediates derived from degradation of poly(A)-deficient molecules could offer clues regarding decay pathways, but these intermediates have not been readily detected. Cell-free mRNA decay systems have proven useful in analyses of decay pathways because decay intermediates are rather stable in vitro. Cell-free systems indicate that many mRNAs decay by a sequential 3'-5' pathway because 3'-terminal decay intermediates form following deadenylation. However, if 3'-terminal, in vitro decay intermediates reflect a biologically significant aspect of mRNA turnover, then similar intermediates should be present in cells. Here, I have compared the in vivo and in vitro decay of mRNA encoded by the c-myc proto-oncogene. Its decay both in vivo and in vitro occurs by rapid removal of the poly(A) tract and generation of a 3'-terminal decay intermediate. These data strongly suggest that a 3'-5' pathway contributes to turnover of c-myc mRNA in cells. It is likely that 3'-5' decay represents a major turnover pathway in mammalian cells.

Base Sequence↗
PubMed2000

Activation of the human asparagine synthetase gene by the amino acid response and the endoplasmic reticulum stress response pathways occurs by common genomic elements.

The human asparagine synthetase (AS) gene is transcriptionally regulated by amino acid deprivation (amino acid response, AAR) and the endoplasmic reticulum stress response (ERSR), also known as the unfolded protein response pathway. The results reported here document the novel observation that induction of the AS gene by the AAR and ERSR pathways occurs via the same set of genomic elements. Data supporting this conclusion include transient transfection of AS promoter/reporter gene constructs that illustrate that the transcriptional control elements used by both pathways are contained with nucleotides -111 to -34 of the AS promoter. In vivo footprinting analysis of this region identified six specific protein-binding sites. Within two of these sites, altered footprinting was observed following amino acid or glucose deprivation, but the patterns were identical for both the AAR and the ERSR pathway. Site-directed mutation of individual nucleotides within these two binding sites confirmed their importance for regulated transcription, and none of the mutations resulted in loss of response of only one pathway. Neither of these two sites corresponds to a recently identified ERSR cis-element, nor do they contain consensus sequences for known transcription factors. Collectively, the data document that there are at least two independent transcriptional mechanisms for gene activation by the ERSR pathway, one of which terminates at the same genomic elements used by the AAR pathway.

Amino Acids↗
PubMed2000

Signaling pathways to the assembly of an interferon-beta enhanceosome. Chemical genetic studies with a small molecule.

Small molecules that modulate specific protein functions are valuable tools for dissecting complex signaling pathways. Here, we identified a small molecule that induces the assembly of the interferon-beta (IFN-beta) enhanceosome by stimulating all the enhancer-binding activator proteins: ATF2/c-JUN, IRF3, and p50/p65 of NF-kappaB. This compound stimulates mitogen-activated protein kinase kinase kinase 1 (MEKK1), which is a member of a family of proteins involved in stress-mediated signaling pathways. Consistent with this, MEKK1 activates IRF3 in addition to ATF2/c-JUN and NF-kappaB for the assembly of the IFN-beta enhanceosome. MEKK1 activates IRF3 through the c-JUN amino-terminal kinase (JNK) pathway but not the p38 and IkappaB kinase (IKK) pathway. Taken together with previous observations, these results implicate that, for the assembly of an IFN-beta enhanceosome, MEKK1 can induce IRF3 and ATF2/c-JUN through the JNK pathway, whereas it can induce NF-kappaB through the IKK pathway. Thus, specific MEKK family proteins may be able to integrate some of multiple signal transduction pathways leading to the specific activation of the IFN-beta enhanceosome.

Enhancer Elements, Genetic↗
PubMed2000

Calcium and cAMP signals differentially regulate cAMP-responsive element-binding protein function via a Rap1-extracellular signal-regulated kinase pathway.

Two major intracellular signals that regulate neuronal function are calcium and cAMP. In many cases, the actions of these two second messengers involve long term changes in gene expression. One well studied target of both calcium and cAMP signaling is the transcription factor cAMP-responsive element-binding protein (CREB). Multiple signaling pathways have been shown to contribute to the regulation of CREB-dependent transcription, including both protein kinase A (PKA)- and mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK)-dependent kinase cascades. We have previously described a mechanism by which cAMP and calcium influx may stimulate ERKs in neuronal cells. This pathway involves the PKA-dependent activation of the Ras-related small G-protein, Rap1, and subsequent stimulation of the neuronal Raf isoform, B-Raf. In this study, we examined the contribution of the Rap1-ERK pathway to the control of gene transcription by calcium influx and cAMP. Using the PC12 cell model system, we found that both calcium influx and cAMP stimulated CREB-dependent transcription via a Rap1-ERK pathway, but this regulation occurred through distinct mechanisms. Calcium-mediated phosphorylation of CREB through the PKA-Rap1-ERK pathway. In contrast, cAMP phosphorylated CREB via PKA directly but required a Rap1-ERK pathway to activate a component downstream of CREB phosphorylation and CREB-binding protein recruitment. These data suggest that the Rap1/B-Raf signaling pathway may have an important role in the regulation of CREB-dependent gene expression.

3T3 Cells↗