Abstract:
:Because of differences in the downstream signaling patterns of its pathways, the role of the human epidermal growth factor family of receptors (HER) in promoting cell growth and survival is cell line and context dependent. Using two model cell lines, we have studied how the regulatory interaction network among the key proteins of HER signaling pathways may be rewired upon normal to cancerous transformation. We in particular investigated how the transcription factor STAT3 and several key kinases' involvement in cancer-related signaling processes differ between normal 184A1L5 human mammary epithelial (HME) and MDA-MB-231 breast cancer epithelial cells. Comparison of the responses in these cells showed that normal-to-cancerous cellular transformation causes a major re-wiring of the growth factor initiated signaling. In particular, we found that: i) regulatory interactions between Erk, p38, JNK and STAT3 are triangulated and tightly coupled in 184A1L5 HME cells, and ii) STAT3 is only weakly associated with the Erk-p38-JNK pathway in MDA-MB-231 cells. Utilizing the concept of pathway substitution, we predicted how the observed differences in the regulatory interactions may affect the proliferation/survival and motility responses of the 184A1L5 and MDA-MB-231 cells when exposed to various inhibitors. We then validated our predictions experimentally to complete the experiment-computation-experiment iteration loop. Validated differences in the regulatory interactions of the 184A1L5 and MDA-MB-231 cells indicated that instead of inhibiting STAT3, which has severe toxic side effects, simultaneous inhibition of JNK together with Erk or p38 could be a more effective strategy to impose cell death selectively to MDA-MB-231 cancer cells while considerably lowering the side effects to normal epithelial cells. Presented analysis establishes a framework with examples that would enable cell signaling researchers to identify the signaling network structures which can be used to predict the phenotypic responses in particular cell lines of interest.
journal_name
J Cell Commun Signaljournal_title
Journal of cell communication and signalingauthors
Speth Z,Islam T,Banerjee K,Resat Hdoi
10.1007/s12079-017-0389-3subject
Has Abstractpub_date
2017-12-01 00:00:00pages
341-356issue
4eissn
1873-9601issn
1873-961Xpii
10.1007/s12079-017-0389-3journal_volume
11pub_type
杂志文章abstract::Research over the past few years has highlighted the ability of the unfolded protein response (UPR) to minimize the deleterious effects of accumulated misfolded proteins under both physiological and pathological conditions. The endoplasmic reticulum (ER) adapts to endogenous and exogenous stressors by expanding its pr...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-014-0251-9
更新日期:2014-12-01 00:00:00
abstract::We recently reported that transgenic mice with cardiac-restricted overexpression of CCN2/CTGF have substantially increased tolerance towards ischemia/reperfusion injury. The purpose of this study was to investigate to what extent fully differentiated cardiac myocytes are direct targets of CCN2, and to resolve the sign...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-012-0183-1
更新日期:2013-03-01 00:00:00
abstract::Fibrotic diseases are a significant cause of mortality. It is being increasingly appreciated that the cellular microenvironment plays a key role in promoting pathological fibrosis. A previous Bits and Bytes described an elegant series of experiments published by Bruce Riser and colleagues (Am J Pathol. 2009: 174:1725-...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-015-0281-y
更新日期:2015-03-01 00:00:00
abstract::Key pathways like insulin signaling, AMP activated kinase (AMPK) activation and inflammatory signaling are involved in the complex pathological network of hepatic insulin resistance. Our aim is to investigate whether grape seed proanthocyanidins (GSP) and metformin (MET) target any of these pathways in insulin resista...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-013-0210-x
更新日期:2014-03-01 00:00:00
abstract::Extracellular molecules coordinate the multiple signaling pathways spatiotemporally to exchange information between cells during development. Understanding the regulation of these signal molecule-dependent pathways elucidates the mechanism of intercellular crosstalks. CCN2/CTGF is one of the CCN family members that bi...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-018-0487-x
更新日期:2019-03-01 00:00:00
abstract::There is no therapy for chronic fibroproliferative diseases, in spite of the fact that current health statistics suggest that these (which include cardiovascular disease, pulmonary fibrosis, diabetic nephropathy, liver cirrhosis and systemic sclerosis) have been estimated to cause approximately 45% of the deaths in th...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-011-0156-9
更新日期:2012-03-01 00:00:00
abstract::Periostin is a secretory protein with a multi-domain structure, comprising an amino-terminal cysteine-rich EMI domain, four internal FAS 1 domains, and a carboxyl-terminal hydrophilic domain. These adjacent domains bind to extracellular matrix proteins (type I collagen, fibronectin, tenascin-C, and laminin γ2), and BM...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章,评审
doi:10.1007/s12079-017-0422-6
更新日期:2018-03-01 00:00:00
abstract::Mitogen activated protein kinases (MAPKs) play an important role in activation, differentiation and proliferation of macrophages. Macrophages, upon activation, produce large amounts of nitric oxide that inhibit the growth of variety of microorganisms and tumor cells. This nitric oxide which is known to interfere with ...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-008-0021-7
更新日期:2007-12-01 00:00:00
abstract::UNC-5 Homolog B (UNC5B) is a member of the dependence receptor family. This family of receptors can induce two opposite intracellular signaling cascades depending on the presence or absence of the ligand and is thus capable of driving two opposing processes. UNC5B signaling has been implicated in several cancers, wher...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-018-0485-z
更新日期:2019-03-01 00:00:00
abstract::The expression of the CCN family of matricellular proteins is highly dysregulated in connective tissue pathologies such as fibrosis and highly metastatic cancers. Strategies targeting members of this family, especially CCN2, are under development as novel therapeutic approaches to highly metastatic cancers such as pan...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章,评审
doi:10.1007/s12079-016-0321-2
更新日期:2016-06-01 00:00:00
abstract::Pancreatitis is an inflammatory condition of the pancreas which, in its chronic form, involves tissue destruction, exocrine and endocrine insufficiency, increased risk of pancreatic cancer, and an extensive fibrotic pathology which is due to unrelenting collagen deposition by pancreatic stellate cells (PSC). In respon...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-014-0220-3
更新日期:2014-06-01 00:00:00
abstract::Inflammation is a crucial component in the pathogenesis of many vascular diseases, such as atherosclerosis and diabetes. Inflammasomes are intracellular signalling complexes whose activation promotes inflammation. Nucleotide-binding domain and Leucine-rich repeat Receptor containing a Pyrin domain 3 (NLRP3) is a patte...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-017-0396-4
更新日期:2017-09-01 00:00:00
abstract::The Kallikrein Kinin System (KKS) is a vasoactive peptide system with known functions in the maintenance of tissue homeostasis, renal function and blood pressure. The main effector peptide of KKS is Bradykinin (BK). This ligand has two receptors: a constitutive B2 receptor (B2R), which has been suggested to have anti-...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-017-0439-x
更新日期:2018-09-01 00:00:00
abstract::The aim of this study was to investigate the effects of homocysteine (Hcy), a risk factor for cardiovascular diseases, hypertension, stroke and obesity, on expression of CD36 that regulates uptake of oxidized low-density lipoprotein (Ox-LDL) by adipocytes and differentiation of 3T3-L1 cells to adipocytes. Cell viabili...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-015-0316-4
更新日期:2016-03-01 00:00:00
abstract::Erlotinib is an oral tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) pathway. Although our previous study has proved the efficacy of Erlotinib in head and neck squamous cell carcinoma (HNSCC), it has also demonstrated poor clinical response rates and disappointing results in clinical trials for HN...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-020-00546-7
更新日期:2020-12-01 00:00:00
abstract::Lung immaturity is the major cause of morbidity and mortality in premature infants, especially those born <28 weeks of gestation. These infants are at high risk of developing respiratory distress syndrome (RDS), a lung disease caused by insufficient surfactant production and immaturity of saccular/alveolar type II epi...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-017-0443-1
更新日期:2018-03-01 00:00:00
abstract::Connexin43 (Cx43) gap junctions expressed in astrocytes can significantly impact neuronal survival in stroke. However, little is known regarding Cx43 spatial and temporal expression during the initial stages of brain ischemia. Using immunohistochemistry and Western blot analysis, we examined Cx43 spatial and temporal ...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-017-0430-6
更新日期:2018-03-01 00:00:00
abstract::Transforming growth factor beta (TGF-beta) and connective tissue growth factor (CTGF) have been described to induce the production of extracellular matrix (ECM) proteins and have been reported to be increased in different fibrotic disorders. Skeletal muscle fibrosis is a common feature of Duchenne muscular dystrophy (...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-008-0018-2
更新日期:2007-12-01 00:00:00
abstract::CCN proteins play crucial roles in development, angiogenesis, cell motility, matrix turnover, proliferation, and other fundamental cell processes. Early embryonic lethality in CCN5 knockout and over-expressing mice led us to characterize CCN5 distribution in early development. Previous papers in this series showed tha...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-012-0176-0
更新日期:2012-12-01 00:00:00
abstract::PEGylation is a biochemical modification process of bioactive molecules with polyethylene glycol (PEG), which lends several desirable properties to proteins/peptides, antibodies, and vesicles considered to be used for therapy or genetic modification of cells. However, PEGylation of proteins is a complex process and ca...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章,评审
doi:10.1007/s12079-018-0492-0
更新日期:2019-09-01 00:00:00
abstract::CCN3 is a member of the CCN family of cell growth and differentiation regulators that play key roles during embryonic development, and are associated with severe human pathologies. The level of CCN genes' expression is of prognostic value in several types of tumors. In the present manuscript, we report the isolation a...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-007-0009-8
更新日期:2007-09-01 00:00:00
abstract::Non-alcoholic fatty liver disease (NAFLD) is a condition in which fat accumulates in the liver of patients without a prior history of alcohol abuse. The most severe form, nonalcoholic steatohepatitis (NASH), often leads to hepatic fibrosis and cirrhosis with ensuing complications. To date, there is no pharmacologic tr...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-017-0432-4
更新日期:2018-03-01 00:00:00
abstract::It is well-established that the expression of CCN family of matricellular proteins is altered in essentially all cancers and, hence, targeting these proteins may be a novel therapeutic approach to treating these diseases. For example, CCN6 (WISP3) is downregulated in aggressive breast cancers, and this phenomenon appe...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-012-0189-8
更新日期:2013-06-01 00:00:00
abstract::The Rsu1 protein contributes to cell adhesion and migration via its association with the adaptor complex of Integrin linked kinase (ILK), PINCH, and Parvin (IPP), which binds to the cytoplasmic domain of β1 integrins joining integrins to the actin cytoskeleton. Rsu1 binding to PINCH in the IPP complex is required for ...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-018-00504-4
更新日期:2019-09-01 00:00:00
abstract::Hepatocyte exosomes (ExoHep) are proposed to mediate physiological or pathophysiological signaling in a variety of hepatic target cells. ExoHep were purified from the medium of primary mouse hepatocytes or AML12 cells and characterized as ~100 nm nanovesicles that were positive for proteins commonly found in exosomes ...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-017-0421-7
更新日期:2018-03-01 00:00:00
abstract::Cell adhesion and migration are complex processes that require integrin activation, the formation and dissolution of focal adhesion (FAs), and linkage of actin cytoskeleton to the FAs. The IPP (ILK, PINCH, Parvin) complex regulates FA formation via binding of the adaptor protein ILK to β1 integrin, PINCH and parvin. T...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-013-0207-5
更新日期:2013-12-01 00:00:00
abstract::We have recently identified several novel ATP-independent inhibitors that target the extracellular signal-regulated kinase-2 (ERK2) protein and inhibit substrate phosphorylation. To further characterize these compounds, we describe the use of C. elegans as a model organism. C. elegans is recognized as a versatile and ...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-008-0034-2
更新日期:2008-12-01 00:00:00
abstract::The discovery of the gap junction structure, its functions and the family of the "connexin" genes, has been basically ignored by the major biological disciplines. These connexin genes code for proteins that organize to form membrane-associated hemi-channels, "connexons", co-join with the connexons of neighboring cells...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-010-0108-9
更新日期:2011-03-01 00:00:00
abstract::Tumor cells release extracellular vesicles (EVs) into the tumor microenvironment that may facilitate malignant progression and metastasis. Breast carcinoma EVs express high levels of the thrombospondin-1 and signal regulatory protein-α receptor CD47, which is the target of several experimental therapeutics currently i...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-017-0428-0
更新日期:2018-03-01 00:00:00
abstract::Interferon gamma (IFN-ɣ) is a pleiotropic cytokine which plays dual contrasting roles in cancer. Although IFN-ɣ has been clinically used to treat various malignancies, it was recently shown to have protumorigenic activities. Reactive oxygen species (ROS) are overproduced in cancer cells, mainly due to NADPH oxidase ac...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-016-0362-6
更新日期:2017-03-01 00:00:00