Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuregulins are receptor tyrosine kinase ligands that play a critical role in the development of the heart, nervous system, and breast. Unlike many extracellular signaling molecules, such as the neurotrophins, most neuregulins are synthesized as transmembrane proteins. To determine the functions of the highly conserved neuregulin cytoplasmic tail, a yeast two-hybrid screen was performed to identify proteins that interact with the 157-amino acid sequence common to the cytoplasmic tails of all transmembrane neuregulin isoforms. This screen revealed that the neuregulin cytoplasmic tail interacts with the LIM domain region of the nonreceptor protein kinase LIM kinase 1 (LIMK1). Interaction between the neuregulin cytoplasmic tail and full-length LIMK1 was demonstrated by in vitro binding and co-immunoprecipitation assays. Transmembrane neuregulins with each of the three known neuregulin cytoplasmic tail isoforms interacted with LIMK1. In contrast, the cytoplasmic tail of TGF-alpha did not interact with LIMK1. In vivo, neuregulin and LIMK1 are co-localized at the neuromuscular synapse, suggesting that LIMK1, like neuregulin, may play a role in synapse formation and maintenance. To our knowledge, LIMK1 is the first identified protein shown to interact with the cytoplasmic tail of a receptor tyrosine kinase ligand.
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PMID:Transmembrane neuregulins interact with LIM kinase 1, a cytoplasmic protein kinase implicated in development of visuospatial cognition. 968 9

Heregulin (HRG) is a family of polypeptide growth factors derived from alternatively spliced genes. HRG can bind to receptor tyrosine kinases erbB3 and erbB4, thereby inducing erbB3 and erbB4 heterodimerization with erbB2, leading to receptor tyrosine phosphorylation and activating downstream signal transduction. Cell-cell homophilic adhesion (cell aggregation) is important in determining the structural organization and behavior of cells in tissues. In addition, tumor cell homophilic adhesion may affect invasive and metastatic potentials of cells. We report that HRG-beta1 can enhance aggregation of MCF-7 and SKBR3 human breast cancer cells. While investigating the downstream signals involved in HRG-beta1-enhanced cell aggregation, we observed that HRG-beta1 induced tyrosine phosphorylation of erbB2 and crbB3 receptor heterodimers and increased the association of the dimerized receptors with the 85-kDa subunit of phosphatidylinositol 3-kinase (PI3K). HRG-beta also increased the kinase activities of extracellular signal-regulated protein kinase (ERK) and PI3K in these cells. By using the mitogen-activated protein kinase/ERK 1 (MEK1) inhibitor PD98059 and PI3K inhibitors wortmannin and LY294002, we found that blocking the MEK1-ERK pathway had no effect on HRG-pbeta1-enhanced cell aggregation; however, blocking the PI3K pathway greatly inhibited HRG-beta1-mediated cell aggregation. Our study indicated that the HRG-beta1-activated MEK1-ERK pathway has no demonstrable role in the induction of cell aggregation, whereas HRG-beta1-activated PI3K is required for enhancing breast cancer cell aggregation. Because aggregation can contribute to invasion/metastasis phenotype of cancer cells, our results have provided one mechanism by which HRG-beta1-activated signaling of erbB receptors may affect invasive/metastatic properties of MCF-7 and SKBR3 breast cancer cells.
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PMID:Heregulin beta1-activated phosphatidylinositol 3-kinase enhances aggregation of MCF-7 breast cancer cells independent of extracellular signal-regulated kinase. 1019 38

The ErbB2 tyrosine kinase functions as coreceptor for the neuregulin receptors ErbB3 and ErbB4 and can participate in signaling of EGF receptor (ErbB1), interleukin receptor gp130, and G-protein coupled receptors. ErbB2(-/-) mice die at midgestation because of heart malformation. Here, we report a genetic rescue of their heart development by myocardial expression of erbB2 cDNA that allows survival of the mutants to birth. In rescued erbB2 mutants, Schwann cells are lacking. Motoneurons form and can project to muscle, but nerves are poorly fasciculated and disorganized. Neuromuscular junctions form, as reflected in clustering of AChR and postsynaptic expression of the genes encoding the alpha-AChR, AChE, epsilon-AChR, and the RI subunit of the cAMP protein kinase. However, a severe loss of motoneurons on cervical and lumbar, but not on thoracic levels occurs. Our results define the roles of Schwann cells during motoneuron and synapse development, and reveal different survival requirements for distinct motoneuron populations.
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PMID:Peripheral nervous system defects in erbB2 mutants following genetic rescue of heart development. 1052 98

Previous reports have shown that certain anti-HER2 antibodies and heregulin can inhibit clonogenic growth of breast and ovarian cancers that overexpress HER2. Anti-HER2 antibodies bind to HER2 directly, whereas heregulin does not bind to HER2 alone, but rather interacts with HER2 through the formation of heterodimers with HER3 or HER4. The purpose of the present study was to elucidate the mechanisms by which anti-HER2 antibody and heregulin inhibit tumor growth. The anti-HER2 monoclonal antibody (mAb) ID5 was found to block G1-S progression of the cell cycle, whereas heregulin inhibited passage through G2-M. Compatible with the effects on the cell cycle, treatment with mAb ID5 decreased levels of cyclin-dependent kinase (CDK) 2, cyclin E, and CDK6 proteins and reduced cyclin E-CDK2-associated kinase activity; mAb HD5-treated cells had increased p27Kip1 expression and an increased association of p27Kip1 with CDK2. In contrast, treatment with heregulin increased protein levels of CDK2, CDK6, CDC2, and cyclin B1. More Retinoblastoma protein was found in the hypophosphorylated state in the cells treated with mAb ID5, whereas more retinoblastoma protein was in the hyperphosphorylated state in heregulin-treated cells. Heregulin was able to induce cell differentiation as assessed by Oil Red O staining and apoptosis as assessed by sub-G1 peak on flow cytometry and the presence of DNA fragmentation in ApopTag histochemistry staining. Neither differentiation nor apoptosis was observed in the cells treated with mAb ID5. We conclude that anti-HER-2 mAb ID5 and heregulin exert growth inhibition through different mechanisms. In mammary cells overexpressing HER2, anti-HER2 mAb ID5 induces G1 arrest, whereas heregulin induces G2-M arrest, cell differentiation, and apoptosis.
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PMID:Anti-HER2 antibody and heregulin suppress growth of HER2-overexpressing human breast cancer cells through different mechanisms. 1065 57

Akt/PKB is a serine/threonine protein kinase that regulates cell cycle progression, apoptosis and growth factor mediated cell survival in association with tyrosine kinase receptors. The protein is a downstream effector of erbB-2 with implications in breast cancer progression and drug resistance in vitro. We aimed to examine the role of Akt-1 in breast cancer patients, by determining whether the expression (Akt-1) and/or activation (pAkt) were related to prognostic markers and survival. The expression of erbB-2, heregulin beta 1 and Bcl-2 was also assessed by flow cytometry or immunohistochemistry. This study comprised 93 patients, aged <50 who were treated with tamoxifen and/or goserelin. We found that pAkt was associated with lower S-phase fraction (P=0.001) and the presence of heregulin beta 1-expressing stromal cells (P=0.017). Neither Akt-1 nor pAkt was related with other factors. Tumour cells-derived heregulin beta 1 was found mainly in oestrogen receptor negative (P=0.026) and node negative (P=0.005) cases. Survival analysis revealed that pAkt positive patients were more prone to relapse with distant metastasis, independently of S-phase fraction and nodal status (multivariate analysis; P=0.004). The results suggest that activation of Akt may have prognostic relevance in breast cancer.
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PMID:Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. 1187 May 34

Nuclear factor-kappaB (NF-kappaB) is usually maintained in an inactive form in the cytoplasm through its association with inhibitor of kappaB (IkappaB) proteins, and is activated upon stimulation of cells with a variety of signals. However, constitutive activation of NF-kappaB is observed in a number of cancers including breast cancer. The signaling pathways that are involved in constitutive NF-kappaB activation remain largely unknown. Using breast cancer cell lines derived from transgenic mice that overexpress specific oncogene/growth factors in the mammary gland, we show that heregulin but not her2/neu, c-Myc or v-Ha-ras plays a major role in constitutive NF-kappaB activation. Her2/neu potentiated tumor necrosis factor alpha (TNFalpha)-inducible NF-kappaB activation whereas c-Myc potentiated 12-o-tetracecanyolphorbol-13-acetate (TPA)-induced NF-kappaB activation. Heregulin-mediated NF-kappaB activation correlated with phosphorylation of epidermal growth factor receptor (EGFR) and ErbB3 but not her2/neu. Tryphostin AG1517, which inhibits heregulin-mediated phosphorylation of EGFR, her2/neu and ErbB3 reduced NF-kappaB activation. In contrast, emodin, which blocks phosphorylation of her2/neu by heregulin, failed to reduce NF-kappaB activation. These results suggest that heregulin induces NF-kappaB independent of her2/neu. PI3 kinase/AKT, protein kinase A (PKA) and IkappaB kinase appear to be downstream signaling molecules involved in NF-kappaB activation as specific inhibitors of these kinases but not inhibitors of ERK/MAP kinase or protein kinase C reduced heregulin-mediated NF-kappaB activation. Based on these results, we propose that heregulin increases the expression of pro-invasive, pro-metastatic and anti-apoptotic genes in cancer cells through autocrine activation of NF-kappaB, which leads to invasive and drug-resistant growth of breast cancer.
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PMID:Identification of signal transduction pathways involved in constitutive NF-kappaB activation in breast cancer cells. 1196 Mar 79

This study examines whether the serine/threonine protein kinase, Akt, is involved in the crosstalk between the ErbB2 and estrogen receptor-alpha (ER-alpha) pathways. Treatment of MCF-7 cells with 10(-9) M heregulin-beta1 (HRG-beta1) resulted in a rapid phosphorylation of Akt and a 15-fold increase in Akt activity. Akt phosphorylation was blocked by inhibitors of phosphatidylinositol 3-kinase (PI 3-K), by antiestrogens, the protein tyrosine kinase inhibitor, genistein, and by AG825, a selective ErbB2 inhibitor; but not by AG30, a selective EGFR inhibitor. Akt phosphorylation by HRG-beta1 was abrogated by an arginine to cysteine mutation (R25C) in the pleckstrin homology (PH) domain of Akt, and HRG-beta1 did not induce Akt phosphorylation in the ER-negative variant of MCF-7, MCF-7/ADR. Transient transfection of ER-alpha into these cells restored Akt phosphorylation by HRG-beta1, suggesting the requirement of ER-alpha. HRG-beta1 did not activate Akt in MCF-7 cells stably transfected with an anti-ErbB2-targeted ribozyme, further confirming a role for ErbB2. Stable transfection of the cells with a dominant negative Akt or with the R25C-Akt mutant, as well as PI 3-K inhibitors, blocked the effect of HRG-beta1 on ER-alpha expression and activity and on the growth of MCF-7 cells. Stable transfection of MCF-7 cells with a constitutively active Akt mimicked the effect of HRG-beta1. Experiments employing selective ErbB inhibitors demonstrate that the effect of HRG-beta1 on ER-alpha expression and activity is also mediated by ErbB2 and not by EGFR, demonstrating that ErbB2 is the primary mediator of the effects of HRG-beta1 on ER-alpha regulation. Taken together, our data suggest that HRG-beta1, bound to the ErbB2 ErbB3 heterodimer, in the presence of membrane ER-alpha, interacts with and activates PI 3-K/Akt. Akt leads to nuclear ER-alpha phosphorylation, thereby altering its expression and transcriptional activity.
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PMID:Heregulin-beta1 regulates the estrogen receptor-alpha gene expression and activity via the ErbB2/PI 3-K/Akt pathway. 1575 10

ErbB tyrosine kinase receptors mediate mitogenic signal cascade by binding a variety of ligands and recruiting the different cassettes of adaptor proteins. In the present study, we examined heregulin (HRG)-induced signal transduction of ErbB4 receptor and found that the phosphatidylinositol 3'-kinase (PI3K)-Akt pathway negatively regulated the extracellular signal-regulated kinase (ERK) cascade by phosphorylating Raf-1 on Ser(259). As the time-course kinetics of Akt and ERK activities seemed to be transient and complex, we constructed a mathematical simulation model for HRG-induced ErbB4 receptor signalling to explain the dynamics of the regulation mechanism in this signal transduction cascade. The model reflected well the experimental results observed in HRG-induced ErbB4 cells and in other modes of growth hormone-induced cell signalling that involve Raf-Akt cross-talk. The model suggested that HRG signalling is regulated by protein phosphatase 2A as well as Raf-Akt cross-talk, and protein phosphatase 2A modulates the kinase activity in both the PI3K-Akt and MAPK (mitogen-activated protein kinase) pathways.
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PMID:A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling. 1269 3

Neuregulin is reported to stimulate synapse-specific transcription of acetylcholine receptor (AChR) genes in the skeletal muscle fiber by multiple signaling pathways such as ERK, PI3K, and JNK. The co-localization of PKA mRNA with AChR and ErbBs, receptors for neuregulin, at the confined region of synapse implicates the putative role of PKA in neuregulin-induced AChR gene expression. In the present study, we found that mRNA and protein of a regulatory subunit of PKA (PKARIalpha) were concentrated at synaptic sites of the rat sternomastoid muscle fiber, while those of ERK and PI3K were uniformly distributed throughout the muscle fiber. Neuregulin (100 ng/ml) increased both PKA activity in the nucleus and AChRdelta subunit gene transcription in cultured Sol8 myotubes. These increases were significantly blocked by a specific PKA inhibitor H-89 (100 nM) and an adenylcyclase inhibitor SQ 22536 (200 microM) (72.5% and 60.1%, respectively). Furthermore, neuregulin phosphorylated CREB, a well-known down-stream transcription factor of PKA. While H-89 inhibited CREB phosphorylation, H-89 and PD098059 (50 microM), a specific MEK1/2 inhibitor, did not inhibit the phosphorylation of ERK and CREB, respectively, suggesting no cross-talk between PKA and ERK pathways. In conclusion, neuregulin increases AChRdelta subunit gene transcription, in part, by the activation of PKA/CREB, an alternative route to the previously reported ERK signaling pathway.
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PMID:Cyclic AMP-dependent protein kinase A and CREB are involved in neuregulin-induced synapse-specific expression of acetylcholine receptor gene. 1272 21

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays an important role in mediating survival signals in wide variety of neurons and cells. Recent studies show that Akt also regulates metabolic pathways to regulate cell survival. In this study, we reported that cyclin-dependent kinase-5 (Cdk5) regulates Akt activity and cell survival through the neuregulin-mediated PI 3-kinase signaling pathway. We found that brain extracts of Cdk5-/-mice display a lower PI 3-kinase activity and phosphorylation of Akt compared with that in wild type mice. Moreover, we demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. These findings suggest that Cdk5 may exert a key role in promoting neuronal survival by regulating Akt activity through the neuregulin/PI 3-kinase signaling pathway.
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PMID:Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival. 1282 84


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