c-Src Signaling Research Articles

Abstract 4889: Coupling Factor 6 Enhances the Action of Angiotensin II and Causes Insulin Resistance in Mice

The lower values of intracellular pH are commonly observed in the hypertensive states including a high renin state. It is also reported that intracellular acidosis is related to the pathogenesis of diabetes by inducing insulin resistance in the skeletal muscle. We recently showed that the molecular rotary motor F 1 F o complex, ATP synthase, is present at the plasma membrane, and that coupling factor 6 (CF6) forces the backward rotation of F o after binding to F 1 , resulting in cellular acidosis (Hypertension, 2005). Using CF6-overexpressing transgenic (TG) mice and vascular smooth muscle cells (VSMC), we tested the hypothesis that CF6 enhances the action of angiotensin II (AngII) and causes insulin resistance. In TG mice, the introduced gene of human CF6 was expressed in overall tissues, and upregulated by 2 times. In the mesenteric arterioles isolated from TG mice, Ang II-induced vasoconstriction was enhanced compared with WT mice (p<0.05). Blockade of CF6 with its specific antibody remarkably attenuated the Ang II-induced vasoconstriction by 85±5% in TG mice and by 79±5% in WT mice, thereby eliminating the difference in contraction. In CF6-overexpressing (spontaneously hypertensive rats, SHR) VSMC, Ang II (10 −7 M)-induced increase in the spike phase of [Ca 2+ ] i was higher compared with control (Wistar Kyoto rats) VSMC. In VSMC with a high affinity CF6 receptor (SHR), Ang II (10 −7 M)-induced increase in the spike phase of [Ca 2+ ] i was enhanced by the presence of CF6 at 10 −7 M. All were blocked by PP1 at 50 μ M, a c-Src inhibitor. When the mice were fed with high sucrose diet (20%) for 8 weeks, the TG mice exhibited insulin resistance: In glucose-tolerance test, the plasma glucose level was higher until 1.5 hours (p < 0.05, two-way ANOVA), and insulin level at 1 hour was higher in TG mice (1111 ± 118 vs 400 ± 54 pg/ml, p < 0.05). The TG mice exhibited no change in tyrosine phosphorylation of β subunit of insulin receptor but the decreases in the protein expression of insulin receptor substrate-1 by 64 ± 9%, phosphatidylinositol-3 kinase activity, Akt phosporylation, and the plasma membrane GLUT-4 protein by 69 ± 11% in the skeletal muscle (n = 5, all p < 0.05). These indicate that CF6 enhances the action of AngII by c-Src signaling and thereby causes diet-induced insulin resistance in mice.

An integrin αvβ3–c-Src oncogenic unit promotes anchorage-independence and tumor progression

Integrins regulate adhesion-dependent growth, survival and invasion of tumor cells. In particular, expression of integrin αvβ3 is associated with progression of a variety of human tumors. Here, we reveal a novel adhesion-independent role for integrin αvβ3 in pancreatic cancer and other carcinomas. Specifically, αvβ3 expressed in carcinoma cells enhanced anchorage-independent tumor growth in vitro and increased lymph node metastases in vivo. This required recruitment of c-src to the β3 integrin cytoplasmic tail, leading to c-src activation, crk-associated substrate (CAS) phosphorylation and tumor cell survival that, surprisingly, was independent of cell adhesion or focal adhesion kinase (FAK) activation. Reduced expression of endogenous αvβ3 or c-src not only suppressed anchorage-independent growth, but also decreased metastasis in vivo, yet did not affect migration/invasion. These data define an unexpected role for an integrin as a mediator of anchorage-independence suggesting that an αvβ3/c-src signaling module may account for the aggressive behavior of αvβ3-expressing tumors in man.

TRIM31 interacts with p52 Shc and inhibits Src-induced anchorage-independent growth

Tripartite motif-containing protein (TRIM) family proteins are involved in a broad range of biological processes and, consistently, their alterations result in diverse pathological conditions such as genetic diseases, viral infection and cancer development. In this study, we found that one of the TRIM family proteins, TRIM31, is highly expressed in the gastrointestinal tract and interacts with p52 Shc, one of the signal transducers. We also found by a binding assay that almost the whole region other than the RING domain is required for the binding to p52 Shc but found by pulse-chase analysis that overexpression of TRIM31 does not affect the stability of p52 Shc. Moreover, we found that overexpression of TRIM31 suppresses anchorage-independent cell growth induced by the active form of c-Src. These results suggest that TRIM31 attenuates c-Src signaling via p52 Shc under anchorage-independent growth conditions and is potentially associated with growth activity of cells in the gastrointestinal tract.

Neurite Outgrowth is Dependent on the Association of c-Src and Lipid Rafts

Regulation of neurite outgrowth is an important aspect not only for proper development of the nervous system but also for tissue regeneration after nerve injury and the treatment of neuropathological conditions. Here, we report that neurite outgrowth in cortical neuron and neuro 2A (N2A) cell was dependent on intact lipid rafts, as well as the enhanced localization of c-Src in the lipid rafts. Src inhibition or lipid rafts disruption could specifically block c-Src phosphorylation profile, pY416 Src increase and pY529 Src decrease, they also resulted in pY529 Src and c-terminal Src kinase (Csk) partition out of lipid rafts. Thus, we concluded that c-Src signal cascades within the lipid rafts is crucial for efficient neurite outgrowth.

Neuronal Guidance Protein Netrin-1 Induces Differentiation in Human Embryonal Carcinoma Cells

Pluripotent cells within embryonal carcinoma (EC) can differentiate in vivo or in vitro on treatment with specific agents. Differentiating EC cells express lower levels of stem cell-related genes, such as Cripto-1. We show that migration of human EC cells (NTERA/2 and NCCIT) can be reduced following treatment with the guidance molecule Netrin-1. Moreover, Netrin-1 treatment increased the levels of beta-III tubulin, glial filament acidic protein, Nestin, and gamma-aminobutyric acid and reduced the expressions of Cripto-1, Nanog, and Oct4 in EC cells. These Netrin-1-induced effects in the EC cells were mediated via binding of Netrin-1 to the Neogenin receptor and activation of SHP-2, resulting in increased levels of inactive phosphorylated c-src((Y527)). These results suggest that Netrin-1 can induce neuroectodermal-like differentiation of human EC cells by affecting c-src signaling via SHP-2 activation and regulation of Nanog, Oct4, and Cripto-1 expressions.

Mislocalization of cell–cell adhesion complexes in tamoxifen-resistant breast cancer cells with elevated c-Src tyrosine kinase activity

c-Src activation has been implicated in metastasis of tamoxifen-resistant breast cancer. Here we investigated how c-Src activity affects cell adhesion using a tamoxifen-resistant variant of MCF-7 cells (MTR-3) containing elevated c-Src activity. In MTR-3 cells, adhesion proteins β-catenin and E-cadherin are mislocalized, forming novel structures perpendicular to cell–cell junctions. c-Src is associated with β-catenin/E-cadherin complexes and β-catenin tyrosine phosphorylation is enhanced. Blocking c-Src tyrosine kinase activity decreased β-catenin tyrosine phosphorylation and restored localization of β-catenin and E-cadherin at cell–cell junctions. These findings suggest that inhibition of c-Src signaling may prevent metastasis of tamoxifen-resistant breast cancer.

Anti-Thrombotic Effects of Targeting Outside-in αIIbβ3 Signaling in Platelets

Platelet activation by agonists stimulates high affinity binding of adhesive ligands, such as fibrinogen, to integrin αIIbβ3. In turn, ligand binding initiates Src kinase-dependent outside-in signaling, platelet spreading on sub-endothelial matrices, and platelet aggregation. Short-term integrin blockade by parenteral αIIbβ3 antagonists is effectively anti-thrombotic in certain clinical situations, but long-term blockade by oral αIIbβ3 antagonists has been problematic. As an alternative approach, we evaluated the feasibility of disrupting outside-in αIIbβ3 signaling in vivo. A “β3(Δ760-762)” knock-in mouse was generated that lacked the three C-terminal β3 amino acid residues (RGT) necessary for αIIbβ3-dependent c-Src signaling, but retained β3 residues necessary for agonist- and talin-dependent fibrinogen binding. β3(Δ760-762) mice were compared with wild-type β3+/+ littermates, β3+/− heterozygotes, and “β3/β1(EGK)” knock-in mice where β3 RGT was replaced by three C-terminal residues in β1 (EGK) to potentially enable outside-in integrin signaling by certain Src kinases other than c-Src. Whereas β3+/+, β3+/− and β3/β1(EGK) platelets spread and underwent tyrosine phosphorylation normally on fibrinogen, β3(Δ760-762) platelets spread poorly and exhibited reduced tyrosine phosphorylation of c-Src substrates, including the β3 cytoplasmic domain itself (Tyr-747). Furthermore, unlike the three groups of control mice, all of the β3(Δ760-762) mice tested were protected from carotid artery occlusive thrombosis following vessel injury with FeCl3. The median tail bleeding time for the β3(Δ760-762) mice was approximately two-fold longer than that of the control mice. However, β3(Δ760-762) mice did not exhibit spontaneous bleeding, excess bleeding after surgical exposure of the carotid artery, fecal blood loss or anemia. Fibrinogen binding to β3(Δ760-762) platelets was normal in response to saturating concentrations of agonists to the PAR4 thrombin receptor or the GP VI collagen receptor; however, responses to ADP were impaired. These studies establish that deletion of β3 RGT disrupts outside-in αIIbβ3 signaling and confers protection from arterial thrombosis in vivo. Currently available anti-platelet drugs either inhibit agonist-induced activation of αIIbβ3 or block fibrinogen binding to the integrin. The studies reported here suggest that targeting outside-in αIIbβ3 signaling may represent an alternative anti-thrombotic strategy.

Novel actions of estrogen to promote proliferation: Integration of cytoplasmic and nuclear pathways

Both steroids and growth factors stimulate proliferation of steroid-dependent tumor cells, and interaction between these signaling pathways occurs at several levels. Steroid receptors are classified as ligand-activated transcription factors, and steps by which they activate target gene transcription are well understood. Several steroid responses have now been functionally linked to other intracellular signaling pathways, including c-Src or tyrosine kinase receptors. Steroids such as 17β-estradiol (E2), via binding to cytoplasmic or membrane-associated receptors, were also shown to rapidly activate intracellular signaling cascades such as ERK, PI3K and STATs. These E2-stimulated phosphorylations can then contribute to altered tumor cell function. ER-positive breast cancer cells, in which proliferation is stimulated by E2 and suppressed by antiestrogens, have been of particular interest in dissecting nuclear and cytoplasmic roles of estrogen receptors (ER). In some cell contexts, ER interacts directly with the intracellular tyrosine kinase c-Src and other cytoplasmic signaling and adaptor molecules, such as Shc, PI3K, MNAR, and p130 Cas. Although the hierarchy among these associations is not known, it is clear that c-Src plays a fundamental role in both growth factor and E2-stimulated cell growth, and this may also require other growth factor receptors such as those for EGF or IGF-1. STAT transcription factors represent one pathway to integrate E2 cytoplasmic and nuclear signaling. STAT5 is phosphorylated in the cytoplasm at an activating tyrosine in response to E2 or EGF, and then is translocated to the nucleus to stimulate target gene transcription. E2 stimulates recruitment of STAT5 and ER to the promoter of several proliferative genes, and STAT5 knockdown prevents recruitment of either protein to these promoters. STAT5 activation by E2 in breast cancer cells requires c-Src and EGF receptor, and inhibition of c-Src or EGFR, or knockdown of STAT5, prevents E2 stimulation of several genes and breast cancer cell proliferation. Hyperactivation of the growth factor receptor-c-Src pathway can in some contexts decrease growth responses to E2, or render cells and tumors resistant to suppressive actions of endocrine therapies. Crosstalk between growth factors and steroids in both the cytoplasm and nucleus may thus have a profound impact on complex biological processes such as cell growth, and may play a significant role in the treatment of steroid-dependent breast cancers.

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Hsp90 inhibitors are being evaluated extensively in patients with advanced cancers. However, the impact of Hsp90 inhibition on signaling pathways in normal tissues and the effect that this may have on the antitumor activity of these molecularly targeted drugs have not been rigorously examined. Breast and prostate carcinomas are among those cancers that respond to Hsp90 inhibitors in animal xenograft models and in early studies in patients. Because these cancers frequently metastasize to bone, it is important to determine the impact of Hsp90 inhibitors in the bone environment. In the current study, we show that, in contrast to its activity against prostate cancer cells in vitro and its inhibition of s.c. prostate cancer xenografts, the Hsp90 inhibitor 17-AAG stimulates the intraosseous growth of PC-3M prostate carcinoma cells. This activity is mediated not by a direct effect on the tumor but by Hsp90-dependent stimulation of osteoclast maturation. Hsp90 inhibition transiently activates osteoclast Src kinase and promotes Src-dependent Akt activation. Both kinases are key drivers of osteoclast maturation, and three agents that block osteoclastogenesis, the Src inhibitor dasatinib, the bisphosphonate alendronate, and the osteoclast-specific apoptosis-inducer reveromycin A, markedly reduced 17-AAG-stimulated tumor growth in bone. These data emphasize the importance of understanding the complex role played by Hsp90 in regulating signal transduction pathways in normal tissues as well as in cancer cells, and they demonstrate that drug-dependent modulation of the local tumor environment may profoundly affect the antitumor efficacy of Hsp90-directed therapy.

Role of PELP1/MNAR Signaling in Ovarian Tumorigenesis

Emerging evidence suggests that nuclear receptor (NR) coregulators have potential to act as master genes and their deregulation can promote oncogenesis. Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1/MNAR) is a novel NR coregulator. Its expression is deregulated in hormone-driven cancers. However, the role of PELP1/MNAR in ovarian cancer progression remains unknown. Analysis of serial analysis of gene expression data suggested deregulation of PELP1/MNAR expression in ovarian tumors. Western analysis of PELP1/MNAR in normal and serous ovarian tumor tissues showed 3- to 4-fold higher PELP1/MNAR expression in serous tumors compared with normal ovarian tissues. To examine the significance of PELP1/MNAR in ovarian cancer progression, we have generated model cells that overexpress PELP1/MNAR and ovarian cancer cells in which PELP1/MNAR expression is down-regulated by stable expression of PELP1/MNAR-specific shRNA. Down-regulation of PELP1/MNAR in cancerous ovarian model cells (OVCAR3) resulted in reduced proliferation, affected the magnitude of c-Src and protein kinase B (AKT) signaling, and reduced tumorigenic potential of ovarian cancer cells in a nude mouse model. PELP1/MNAR overexpression in nontumorigenic immortalized surface epithelial cells (IOSE cells) promoted constitutive activation of c-Src and AKT signaling pathways and promoted anchorage-independent growth. Immunohistochemical studies using human ovarian cancer tissue arrays (n = 123) showed that PELP1/MNAR is 2- to 3-fold overexpressed in 60% of ovarian tumors, and PELP1/MNAR deregulation occurs in all different types of ovarian cancer. Collectively, these results suggest that PELP1/MNAR signaling plays a role in ovarian cancer cell proliferation and survival, and that its expression is deregulated in ovarian carcinomas.

Signal Transducer and Activator of Transcription 5b, c-Src, and Epidermal Growth Factor Receptor Signaling Play Integral Roles in Estrogen-Stimulated Proliferation of Estrogen Receptor-Positive Breast Cancer Cells

17beta-Estradiol (E2) acts through the estrogen receptor alpha (ERalpha) to stimulate breast cancer proliferation. Here, we investigated the functional relationship between ERalpha and signal transducer and activator of transcription (STAT)5b activity in ER+ MCF-7 and T47D human breast cancer cells after specific knockdown of STAT5b. STAT5b small interfering RNA (siRNA) inhibited E2-induced bromodeoxyuridine (BrdU) incorporation in both cell lines, as well as the E2-induced increase in MCF-7 cell number, cyclin D1 and c-myc mRNA, and cyclin D1 protein expression, indicating that STAT5b is required for E2-stimulated breast cancer proliferation. E2 treatment stimulated STAT5b tyrosine phosphorylation at the activating tyrosine Y699, resulting in increased STAT5-mediated transcriptional activity, which was inhibited by a Y669F STAT5b mutant. E2-induced STAT5-mediated transcriptional activity was inhibited by overexpressing a kinase-defective epidermal growth factor receptor (EGFR), or the EGFR tyrosine kinase inhibitor tyrphostin AG1478, indicating a requirement for EGFR kinase activity. Both E2-induced STAT5b tyrosine phosphorylation and STAT5-mediated transcription were also inhibited by the ER antagonist ICI 182,780 and the c-Src inhibitor PP2, indicating additional requirements for the ER and c-Src kinase activity. EGFR and c-Src kinase activities were also required for E2-induced cyclin D1 and c-myc mRNA. Together, these studies demonstrate positive cross talk between ER, c-Src, EGFR, and STAT5b in ER+ breast cancer cells. Increased EGFR and c-Src signaling is associated with tamoxifen resistance in ER+ breast cancer cells. Here we show that constitutively active STAT5b not only increased basal DNA synthesis, but also conferred tamoxifen resistance. Because STAT5b plays an integral role in E2-stimulated proliferation and tamoxifen resistance, it may be an effective therapeutic target in ER+ breast tumors.

Regulation of Cripto-1 Signaling and Biological Activity by Caveolin-1 in Mammary Epithelial Cells

Human and mouse Cripto-1 (CR-1/Cr-1) proteins play an important role in mammary gland development and tumorigenesis. In this study, we examined the relationship between Cripto-1 and caveolin-1 (Cav-1), a membrane protein that acts as a tumor suppressor in the mammary gland. Cripto-1 was found to interact with Cav-1 in COS7 cells and mammary epithelial cells. Using EpH4 mouse mammary epithelial cells expressing Cr-1 (EpH4 Cr-1) or Cr-1 and Cav-1 (EpH4 Cr-1/Cav-1), we demonstrate that Cav-1 expression markedly reduced the ability of Cr-1 to enhance migration, invasion, and formation of branching structures in EpH4 Cr-1/Cav-1 cells as compared to EpH4 Cr-1 cells. Furthermore, coexpression of Cav-1 together with Cr-1 in EpH4 Cr-1/Cav-1 cells inhibited Cr-1-mediated activation of c-src and mitogen-activated protein kinase signaling pathways. Conversely, primary mammary epithelial cells isolated from Cav-1 null(-/-)/mouse mammary tumor virus-CR-1 transgenic animals showed enhanced motility and activation of mitogen-activated protein kinase and c-src as compared to Cav-1(+/-)/CR-1 mammary cells. Finally, mammary tumors derived from mouse mammary tumor virus-CR-1 mice showed a dramatic reduction of Cav-1 expression as compared to mammary tissue from normal FVB/N mice, suggesting that in vivo Cav-1 is down-regulated during the process of CR-1-mediated mammary tumorigenesis.

Shifting from Spreading to Retraction

Integrin signaling has been implicated in both cell spreading (mediated through the small GTP-binding proteins Rac and cdc42) and cell retraction (mediated through RhoA). However, the mechanism whereby integrin temporally regulates these opposing processes--which must be coordinated in cell migration and wound repair--has been unclear. Noting that calpain cleavage of the cytoplasmic domain of integrin β 3 is inhibited by tyrosine phosphorylation at Y 759 , Flevaris et al . expressed a phosphorylation-mimicking integrin β 3 mutant in Chinese hamster ovary (CHO) cells, along with the wild-type integrin α IIb subunit, to investigate the role of calpain cleavage in integrin signaling. After determining that this R760E mutant was in fact resistant to calpain cleavage when expressed in CHO cells adherent to fibrinogen, the authors showed that cell-mediated clot retraction was inhibited with the R760E mutant cells, whereas cell spreading on fibrinogen was enhanced. In contrast, a deletion mutant that mimicked calpain cleavage exhibited defective cell spreading. RhoA was activated in cells with cleaved integrin β 3 , and pharmacological analysis indicated that defective spreading in the deletion mutant depended on activation of RhoA and Rho-dependent kinase (ROCK)-mediated retraction. A combination of pharmacological analysis and investigation of a dominant-negative c-Src mutant revealed that integrin β 3 -dependent c-Src signaling inhibited RhoA activation, thereby promoting cell spreading; integrin β 3 cleavage disrupted its binding to c-Src, thereby relieving its inhibition of RhoA and stimulating retraction. Thus, the authors propose that the phosphorylation-regulated cleavage of the integrin β 3 cytoplasmic domain by calpain switches the integrin β 3 signal to promote retraction instead of spreading. P. Flevaris, A. Stojanovic, H. Gong, A. Chishti, E. Welch, X. Du, A molecular switch that controls cell spreading and retraction. J. Cell Biol. 179 , 553-565 (2007). [Abstract] [Full Text]

Caveolin-1 Reduces Osteosarcoma Metastases by Inhibiting c-Src Activity and Met Signaling

Caveolin-1 (Cav-1) is highly expressed in normal osteoblasts. This article reports that Cav-1 down-regulation is part of osteoblast transformation and osteosarcoma progression and validates its role as oncosuppressor in human osteosarcoma. A survey of 6-year follow-up indicates a better overall survival for osteosarcoma expressing a level of Cav-1 similar to osteoblasts. However, the majority of primary osteosarcoma shows significantly lower levels of Cav-1 than normal osteoblasts. Accordingly, Met-induced osteoblast transformation is associated with Cav-1 down-regulation. In vitro, osteosarcoma cell lines forced to overexpress Cav-1 show reduced malignancy with inhibited anchorage-independent growth, migration, and invasion. In vivo, Cav-1 overexpression abrogates the metastatic ability of osteosarcoma cells. c-Src and c-Met tyrosine kinases, which are activated in osteosarcoma, colocalize with Cav-1 and are inhibited on Cav-1 overexpression. Thus, Cav-1 behaves as an oncosuppressor in osteosarcoma. Altogether, data suggest that Cav-1 down-modulation might function as a permissive mechanism, which, by unleashing c-Src and Met signaling, enables osteosarcoma cells to invade neighboring tissues. These data strengthen the rationale to target c-Src family kinases and/or Met receptor to improve the extremely poor prognosis of metastatic osteosarcoma.

Negative autoregulation of RANKL and c-Src signaling in osteoclasts

Osteoclasts are multinucleated giant cells that are responsible for bone matrix degradation. The mechanisms of differentiation and bone resorption processes in osteoclasts have been investigated extensively at the molecular level. In particular, the discovery of the receptor activator of the nuclear factor-κB ligand (RANKL) signaling cascade built the foundation for subsequent studies to understand the various aspects of osteoclasts. RANKL, as an essential factor for differentiation and bone resorption, regulates a number of molecules to orchestrate differentiation as well as the function of osteoclasts. Most of those molecules have been proven to play positive roles in osteoclastogenesis and/or bone resorption; however, studies showing that RANKL could also induce autoregulatory signals and modulate its own signaling cascades have been accumulating. Such a regulatory mechanism(s) may contribute to prevent the excess formation and activation of osteoclasts and thereby, to control bone metabolism as a whole. We newly identifi ed such a mechanism in c-Src, and its signifi cance is discussed in the context of RANKL-induced osteoclastogenesis. RANKL signaling in osteoclastogenesis

E-Cadherin Adhesion Activates c-Src Signaling at Cell–Cell Contacts

Cadherin-based cell-cell contacts are prominent sites for phosphotyrosine signaling, being enriched in tyrosine-phosphorylated proteins and tyrosine kinases and phosphatases. The functional interplay between cadherin adhesion and tyrosine kinase signaling, however, is complex and incompletely understood. In this report we tested the hypothesis that cadherin adhesion activates c-Src signaling and sought to assess its impact on cadherin function. We identified c-Src as part of a cadherin-activated cell signaling pathway that is stimulated by ligation of the adhesion receptor. However, c-Src has a biphasic impact on cadherin function, exerting a positive supportive role at lower signal strengths, but inhibiting function at high signal strengths. Inhibiting c-Src under circumstances when it is activated by cadherin adhesion decreased several measures of cadherin function. This suggests that the cadherin-activated c-Src signaling pathway serves positively to support cadherin function. Finally, our data implicate PI3-kinase signaling as a target for cadherin-activated c-Src signaling that contributes to its positive impact on cadherin function. We conclude that E-cadherin signaling is an important activator of c-Src at cell-cell contacts, providing a key input into a signaling pathway where quantitative changes in signal strength may result in qualitative differences in functional outcome.

Ionotropic Stress and Integrin

Cardiac remodeling is an adaptive response to chronically increased wall stress. Adaptive remodeling of the myocardium, caused either by increased workload or ionotropic stress, requires mediators for the communication of cardiac cells with their surrounding extracellular matrix.1 Integrins are likely candidates that transduce increased mechanical force into the intracellular biochemical signals. In this issue of Hypertension , Krishnamurthy et al2 report a potential role of myocardial β1-integrin in the adaptive and maladaptive remodeling that occurs in isoproterenol-induced left ventricular hypertrophy. To place the findings of this study in context with emerging studies regarding myocardial remodeling and the progression to left ventricular failure, a brief review of the biology of β1-integrin with respect to myocardial hypertrophy and remodeling is presented here. Integrins are heterodimeric cell-surface receptors composed of α and β subunits that function as adhesive and signaling molecules, as well as mechanotransducers.3 In noncardiac cells, it has been demonstrated that integrins respond to abnormal strain in a manner similar to that which would be found during pressure or volume overload in the heart.4 Integrins are expressed in various types of cells, including leukocytes, endothelial cells, vascular smooth muscle …

β 3 Integrin deficiency promotes cardiac hypertrophy and inflammation

Cardiac hypertrophy commonly develops in response to pressure overload and is associated with increased mortality. Mechanical stress in the heart can result in the activation of transmembrane integrin αβ heterodimers that are expressed in cardiomyocytes. Once activated, integrins stimulate focal adhesion kinase, Grb2, c-src, and other signaling molecules to promote cardiomyocyte growth and gene expression. Mechanical stress can also promote cardiac inflammation that may be mediated, in part, by the activation of integrins expressed in blood-borne cells. To address the role of one integrin, β 3, in the pathogenesis of cardiac hypertrophy, β 3 −/− mice were examined. β 3 −/− Mice developed moderate spontaneous cardiac hypertrophy associated with systolic and diastolic dysfunction, and these abnormalities were exacerbated by transverse aortic constriction. In addition, β 3 −/− mice developed mild cardiac inflammation with infiltrating macrophages at baseline that was markedly worsened by pressure overload. Bone marrow transplantation experiments showed that blood-borne cells were at least partially responsible for the cardiac hypertrophy and inflammation observed in β 3 −/− mice. These results suggest that α vβ 3 expression in bone marrow has a generalized suppressive effect on cardiac inflammation.

JNK/NFATおよびc-Srcシグナルによる破骨細胞分化、機能の調節

JNK/NFATおよびc-Srcシグナルによる破骨細胞分化、機能の調節

MUC1 cytoplasmic tail: a potential therapeutic target for ovarian carcinoma

Ovarian cancer is often a lethal disease, since the occult progression of the tumor within the peritoneal cavity results in late diagnosis and treatment failure. The identification of molecular events specific to metastasis is critical for the development of effective therapies. MUC1 is aberrantly overexpressed by most ovarian cancer and regarded as a molecular target for ovarian cancer. This review focuses on the latest advances regarding a signaling region in the MUC1 C-terminal subunit-mediated c-Src signaling pathways in malignant transformation, invasion and metastasis. Disruption of MUC1-C-terminal subunit-associated c-Src signaling by targeting the specific sites might represent a novel immunotherapeutic approach for the treatment of ovarian cancer.