Expression and subcellular distribution of the active form of c-Src tyrosine kinase in differentiating human endometrial stromal cells

Yamamoto, Yurie

doi:10.1093/molehr/8.12.1117

Cited by 17 publications

(18 citation statements)

References 43 publications

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“…This interaction may be facilitated when SRC becomes conformationally open upon dephosphorylation of tyrosine 527 (530 in human). In agreement, with this, we previously reported that decidual SRC becomes activated together with its dephosphorylation on tyrosine 530 [67,72]. Furthermore, it is likely that SRC activation is hormone dependent in decidual hESCs, as withdrawal of E2 and progesterone reduces SRC kinase activity to its basal level and also changes the pattern of tyrosine phosphorylation to that of the unstimulated state [66].…”

Section: D]pyrimidine (Pp1) and 4-amino-5-(4-chlorophenyl)-7-(t-butylsupporting

confidence: 85%

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Molecular and Cellular Mechanisms for Differentiation and Regeneration of the Uterine Endometrium

2008

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Abstract. The human endometrium undergoes cyclical changes including proliferation, differentiation, tissue breakdown, and shedding (menstruation) throughout a woman's reproductive life. The postovulatory rise in ovarian progesterone induces profound remodeling and differentiation of the estradiol-primed endometrium. This change, termed decidualization, is crucial for embryo implantation and maintenance of the pregnancy. To date, activation and crosstalk of cAMP-and progesterone-mediated signaling pathways have emerged as key cellular events to drive integrated changes at both the transcriptome and the proteome levels. This results in the induction and maintenance of the decidual phenotype and function. Our recent series of studies highlights the critical role of SRC kinase activation (v-src sarcoma viral oncogene homolog) and STAT5 (signal transducer and activator of transcription 5) phosphorylation in decidualization. After separation of the functional layer of the differentiated endometrium that follows progesterone withdrawal, i.e., menstruation, the basal layer of the endometrium, under the influence of estradiol, regrows and initiates a unique form of angiogenesis and regenerates a new functional layer. The molecular and cellular mechanisms for this process remain elusive, mainly because of difficulties in reproducing menstrual tissue breakdown, shedding, and subsequent tissue regeneration in vitro. We have recently developed a "humanized" mouse model in which a functional human endometrium is reconstituted. It may be used as an in vivo experimental tool for the study of endometrial angiogenesis and regeneration. This model may also be used to identify and test new therapeutic strategies for endometriosis, endometrial cancer, implantation failure, and infertility related to endometrial dysfunction.

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Section: D]pyrimidine (Pp1) and 4-amino-5-(4-chlorophenyl)-7-(t-butylsupporting

confidence: 85%

“…Furthermore, we found that tyrosine kinase activity of SRC was increased during in vitro decidualization [66]. Subsequent immunohistochemical studies of the human endometrium and pregnancy decidua revealed that the kinase-active form of SRC was strongly expressed in decidual cells in humans and mice [67,68].…”

Section: Downstream Events Of Camp Signalingmentioning

confidence: 82%

Molecular and Cellular Mechanisms for Differentiation and Regeneration of the Uterine Endometrium

2008

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“…For example, dephosphorylation of Src Tyr-530 by protein tyrosine phosphatases has been proposed as a likely mechanism for its activation (15). Interestingly, Src was found to be dephosphorylated at its inhibitory site Tyr-530 in our phosphoproteome, suggesting potential involvement of β-arrestins in activation of Src in response to AT1aR activation.…”

Section: β-Arrestin-dependent Phosphorylation Events Downstream Of At1armentioning

confidence: 80%

Global phosphorylation analysis of β-arrestin–mediated signaling downstream of a seven transmembrane receptor (7TMR)

Xiao¹,

Sun²,

Kim³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

181

156

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β-Arrestin–mediated signaling downstream of seven transmembrane receptors (7TMRs) is a relatively new paradigm for signaling by these receptors. We examined changes in protein phosphorylation occurring when HEK293 cells expressing the angiotensin II type 1A receptor (AT1aR) were stimulated with the β-arrestin–biased ligand Sar 1 , Ile 4 , Ile 8 -angiotensin (SII), a ligand previously found to signal through β-arrestin–dependent, G protein-independent mechanisms. Using a phospho-antibody array containing 46 antibodies against signaling molecules, we found that phosphorylation of 35 proteins increased upon SII stimulation. These SII-mediated phosphorylation events were abrogated after depletion of β-arrestin 2 through siRNA-mediated knockdown. We also performed an MS-based quantitative phosphoproteome analysis after SII stimulation using a strategy of stable isotope labeling of amino acids in cell culture (SILAC). We identified 1,555 phosphoproteins (4,552 unique phosphopeptides), of which 171 proteins (222 phosphopeptides) showed increased phosphorylation, and 53 (66 phosphopeptides) showed decreased phosphorylation upon SII stimulation of the AT1aR. This study identified 38 protein kinases and three phosphatases whose phosphorylation status changed upon SII treatment. Using computational approaches, we performed system-based analyses examining the β-arrestin–mediated phosphoproteome including construction of a kinase-substrate network for β-arrestin–mediated AT1aR signaling. Our analysis demonstrates that β-arrestin–dependent signaling processes are more diverse than previously appreciated. Notably, our analysis identifies an AT1aR-mediated cytoskeletal reorganization network whereby β-arrestin regulates phosphorylation of several key proteins, including cofilin and slingshot. This study provides a system-based view of β-arrestin–mediated phosphorylation events downstream of a 7TMR and opens avenues for research in a rapidly evolving area of 7TMR signaling.

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“…Our data for active and total Src kinase expression mainly in the cytoplasm of epithelial and stromal cells is similar to what was found by Reissig et al (16), who also demonstrated positive staining for active Src in both glandular epithelium and stromal compartments of breast carcinoma tissues. Yamamoto et al (26) found that in proliferative endometrium, active Src expression was detected mainly in glandular epithelium and that stromal Src exhibited perinuclear localization. In secretory phase endometrium, active Src was detected in both the stroma and glandular epithelium (26).…”

Section: Discussionmentioning

confidence: 99%

Src Kinase and Mitogen-Activated Protein Kinases in the Progression from Normal to Malignant Endometrium

Desouki

Rowan

2004

Clinical Cancer Research

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Purpose: The purpose of this research was to determine whether a correlation exists between the levels of activated mitogen-activated protein kinase (MAPK) and Src kinases and the progression from normal to malignant endometrium.Experimental Design: We measured total and phosphorylated levels for extracellular signal-regulated kinase 1/2, p38, stress-activated protein kinase/c-Jun NH 2 -terminal kinase, and Src kinases from 33 frozen endometrial adenocarcinomas and 38 benign endometrial specimens by quantitation of signals from Western blots using antibodies against these kinases.Results: Elevated phospho-extracellular signal-regulated kinase 1/2 (150 ؎ 40 versus 46 ؎ 7; P ‫؍‬ 0.03), phosphoSrc (28 ؎ 5 versus 4 ؎ 1), and phospho-p38 (131 ؎ 16 versus 27 ؎ 7; P < 0.001) was detected in benign versus malignant endometrium when the Western blot signal of activated kinase was normalized to total kinase levels and ␤ actin. A modest increase in active c-Jun NH 2 -terminal kinase was detected in carcinoma versus benign specimens (51 ؎ 13 versus 43 ؎ 10; P ‫؍‬ 0.8). Expression of total kinases (normalized to ␤-actin) was higher in carcinoma versus benign specimens, respectively (extracellular signal-regulated kinase 1/2, 9 ؎ 2 versus 0.7 ؎ 0.1; Src, 7 ؎ 2 versus 0.4 ؎ 0.1; stress-activated protein kinase c-Jun NH 2 -terminal kinase, 2 ؎ 0.4 versus 0.2 ؎ 0.02; P < 0.001; and p38, 1 ؎ 0.2 versus 0.4 ؎ 0.1; P < 0.01). Immunohistochemistry for active and total Src kinases and MAPKs detected positive staining in epithelial and stroma cells.Conclusions: These data demonstrated that, in contrast with breast cancer, the progression from normal to malignant endometrium is not associated with activation of MAPK and Src kinases. Elevation of these active kinases in benign endometrium may contribute to endometrial resistance to the antiestrogen action of tamoxifen.

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Expression and subcellular distribution of the active form of c-Src tyrosine kinase in differentiating human endometrial stromal cells

Cited by 17 publications

References 43 publications

Molecular and Cellular Mechanisms for Differentiation and Regeneration of the Uterine Endometrium

Molecular and Cellular Mechanisms for Differentiation and Regeneration of the Uterine Endometrium

Global phosphorylation analysis of β-arrestin–mediated signaling downstream of a seven transmembrane receptor (7TMR)

Src Kinase and Mitogen-Activated Protein Kinases in the Progression from Normal to Malignant Endometrium

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