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At least 19 recordsLinked to original sources

PubMed2001

Expression of tyrosine kinase receptors Tie-1 and Tie-2 in giant cell tumor of the tendon sheath: a possible role in synovial proliferation.

We have recently demonstrated that Tie-1 and Tie-2 are expressed in synovial cells from rheumatoid arthritis (RA). To elucidate the possible involvement of Tie receptors in synovial proliferation, we analyzed their expression by immunostaining in five cases of giant cell tumor of tendon sheath (GCTTS), which represents a proliferating lesion of synovial cells. Strong immunoreactivity for both Tie-1 and Tie-2, regardless of the individual patient's profile, was observed in all cases of GCTTS. Six sets of double immunohistochemical stainings for Tie-1/Tie-2 and fibronectin, CD68, or CD34 were carried out to determine the phenotype of Tie-1 and Tie-2-positive tumor components. In these studies, both Tie-1 and Tie-2 immunoreactivity were widely observed in the fibronectin-positive fibroblastic and the CD68-positive histiocytic mononuclear cells, as well as in the osteoclast-like giant cells. In tumor vasculature, Tie receptors were expressed in the CD34-positive endothelial cells possessing proliferating cell nuclear antigen (PCNA) immunoreactivity. We also evaluated the correlation of Tie-1/Tie-2 expression and proliferating cells in GCTTS by using double staining of Tie-1/Tie-2 together with PCNA. Overexpression of PCNA immunoreactivity was frequently found in Tie receptors-positive cells with no obvious differences in the expression pattern of Tie-1 and Tie-2. These findings suggest the possible involvement of Tie receptors in the pathogenesis of GCTTS other than solely via their involvement in angiogenesis and subsequent vascularization. It was demonstrated that Tie-2 immunoreactivity was restricted to the fibroblastic, but not histiocytic, phenotype in RA synovium, suggesting different regulatory control of Tie-2 expression in GCTTS and RA synovium. Overexpression of Tie receptors in GCTTS may imply a biological role for these receptors in synovial proliferation.

Adult↗

PubMed2000

Expression of angiopoietin-1, angiopoietin-2, and tie receptors after middle cerebral artery occlusion in the rat.

Vascular endothelial growth factor (VEGF), a key regulator of vasculogenesis and embryonic angiogenesis, was recently found to be up-regulated in an animal model of stroke. Unlike VEGF, angiopoietin (Ang)-1 and -2, their receptor tie-2, and the associated receptor tie-1 exert their functions at later stages of vascular development, i.e., during vascular remodeling and maturation. To assess the role of the angiopoietin/tie family in ischemia-triggered angiogenesis we analyzed their temporal and spatial expression pattern after middle cerebral artery occlusion (MCAO) using in situ hybridization and immunohistochemistry. Ang-1 mRNA was constitutively expressed in a subset of glial and neuronal cells with no apparent change in expression after MCAO. Ang-2 mRNA was up-regulated 6 hours after MCAO and was mainly observed in endothelial cell (EC) cord tips in the peri-infarct and infarct area. Up-regulation of both Ang-2 and VEGF coincided with EC proliferation. Interestingly, EC proliferation was preceded by a transient period of EC apoptosis, correlating with a change in VEGF/Ang-2 balance. Our observation of specific stages of vascular regression and growth after MCAO are in agreement with recent findings suggesting a dual role of Ang-2 in blood vessel formation, depending on the availability of VEGF.

Angiopoietin-1↗

PubMed2002

Abnormal expression of the angiopoietins and Tie receptors in menorrhagic endometrium.

OBJECTIVE: To identify changes in expression of stimulatory and inhibitory factors when normal endometrium becomes menorrhagic. DESIGN: Retrospective blinded immunohistologic study. SETTING: Private research center. PATIENTS: Premenopausal and postmenopausal women with non-menorrhagic and menorrhagic endometrium undergoing curettage or hysterectomy were selected. INTERVENTION(S): Samples of endometrium were obtained from all patients. MAIN OUTCOME MEASURE(S): Expression of angiopoietins 1 and 2, and vascular receptors Tie-1 and Tie-2 and endothelial nitric oxide synthase (eNOS). RESULT(S): Angiopoietin 1 (ANG-1) expression was similar in non-menorrhagic and menorrhagic endometrium. However, there was a significant increase in expression of ANG-2 and its receptor Tie-2 in menorrhagic tissues, which may be important in destabilizing the endometrial vasculature. Tie-1, responsible for endothelial integrity, was also increased in menorrhagic tissues, and is a likely compensatory mechanism for the existing vascular pathology. Expression of eNOS was also increased in menorrhagic women. CONCLUSION(S): Differences in the expression of ANG-2, Tie-2, Tie-1, and eNOS were found in menorrhagic endometrium, which may represent a new target for therapeutic intervention to correct menorrhagic conditions.

Angiogenesis Inducing Agents↗

PubMed1993

Distinct rat genes with related profiles of expression define a TIE receptor tyrosine kinase family.

We have isolated rat cDNAs that encode two related receptor-like tyrosine kinases. One of these receptors, TIE-1, is the rat homolog of a recently described human receptor-like kinase termed TIE (Partanen et al., 1992). The related TIE-2 receptor has the same organization of amino acid sequence motifs characteristic of TIE-1: two immunoglobulin-like domains, three epidermal growth factor (EGF)-like domains and three fibronectin III-like repeats in the extracellular region and a short kinase insert sequence and C-terminal tail in the intracellular region. The amino acid sequences of the intracellular and extracellular regions of TIE-1 and TIE-2 are 79% and 32% identical respectively. Both tie genes are broadly expressed in embryonic, neonatal and adult tissues, accounted for largely by their coexpression in endothelial cells. The tie-2 gene is also uniquely expressed in several additional embryonic tissues, including the lens epithelium and the heart epicardium.

Aging↗

PubMed2000

VEGF, its receptors and the tie receptors in recurrent miscarriage.

The aetiology of recurrent miscarriage (at least three consecutive miscarriages) usually remains unsolved. The vascular endothelial growth factor (VEGF) family of proteins, together with their receptors and the Tie (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains) receptors, are crucial for embryonic development. Therefore, we used immunohistochemistry to analyse the expression of VEGF, the VEGF receptors (VEGFR)-1, -2, and -3, and the Tie-1 and Tie-2 receptors in placental and decidual tissue of women with a history of recurrent miscarriage and missed abortion (MA; n = 12) or blighted ovum (BO; n = 6), and from normal early terminated pregnancies (n = 12). Compared with controls, the MA and BO groups showed: (i) diminished placental trophoblastic VEGF immunoreactivity; (ii) weaker VEGFR-1 and -2 immunoreactivity in decidual vascular endothelium; (iii) reduced placental trophoblastic Tie-1 receptor immunoreactivity; and (iv) reduced decidual vascular endothelial Tie-1 and -2 receptor immunoreactivity. The absence of VEGFR-3 immunoreactivity in decidual vascular endothelium was also noted in all study groups. Interestingly, placental villi from the BO group presented blood vessel-like structures negative for von Willebrand factor, but positive for VEGF, VEGFR-1, -2, -3, Tie-1 and Tie-2 receptor. We conclude that the expression of these antigens may be altered in recurrent miscarriages.

Abortion, Habitual↗

PubMed2006

Vascular endothelial growth factor, its receptors, and the tie receptors in the placental bed of women with preeclampsia, diabetes, and intrauterine growth retardation.

Placental bed vascular function is compromised in pregnancies complicated by preeclampsia (PE), intrauterine growth retardation (IUGR), and maternal diabetes mellitus (DM). We performed an immunohistochemical analysis of vascular endothelial growth factor (VEGF), its receptors (VEGFR) -1 and -2, and the Tie-1 and -2 receptors in cryostat tissue sections of the placental bed from healthy women (n = 5) and women with PE (n = 5), IUGR (n = 5), and DM (n = 5). VEGF immunoreactivity was stable between the study groups. VEGFR-1 immunoreactivity in the myometrial vascular smooth muscle cells was strongest in the controls. In the myometrial cells, the strongest VEGFR-2 immunoreactivity was seen in women with IUGR. In the decidual vascular endothelial cells, the strongest Tie-1 immunoreactivity was observed in healthy women and in those with DM. Alterations in the placental bed expression of VEGFR-1, VEGFR -2, and Tie-1, but not of VEGF and Tie-2, may be associated with PE, IUGR, or DM.

Birth Weight↗

PubMed2000

Immunohistochemical localisation of protein tyrosine kinase receptors Tie-1 and Tie-2 in synovial tissue of rheumatoid arthritis: correlation with angiogenesis and synovial proliferation.

OBJECTIVE: To investigate the involvement of Tie-1 and Tie-2, receptor tyrosine kinases required for angiogenesis, in synovial proliferation and angiogenesis of rheumatoid arthritis (RA). METHODS: Synovial tissues from 10 patients with RA and three control subjects were analysed by double immunohistochemistry and reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Expression of Tie-1 and Tie-2 was seen in all synovia, but predominantly in papillary projected portions. In synovial lining cells, Tie-2 was expressed mainly in the basal layer and frequently colocalised with vimentin and proliferating cell nuclear antigen (PCNA), whereas Tie-1 was also expressed in the superficial layer. In stromal cells, Tie-2 immunoreactivity was restricted to vimentin positive fibroblast-but not macrophage derived cells, whereas Tie-1 expression was not dependent on the phenotype. Tie receptors were also highly expressed in the endothelium and surrounding pericytes of capillaries scattered over the papillary proliferated synovium without notable difference in the expression of the two receptors. Furthermore, Tie positive vessels often overexpressed PCNA. In normal synovia, expression of Tie receptors was restricted to the capillary endothelium. RT-PCR confirmed the expression of Tie-1 and Tie-2 in RA synovial tissues and also in the cultured synoviocytes. CONCLUSION: The results suggest the possible involvement of overexpressed Tie-1 and Tie-2 in synovial lining and stromal cells in the pathophysiology of RA synovitis, probably through distinct mechanisms. Furthermore, expression of Tie receptors in actively growing vasculature may reflect the direct involvement of these receptors in angiogenesis and subsequent vascularisation.

Adult↗

PubMed2006

Differential expression of angiopoietin-1, angiopoietin-2, and Tie receptors in placentas from pregnancies complicated by placenta accreta.

OBJECTIVE: The purpose of this study was to investigate the differential expression of angiopoietin-1, angiopoietin-2, and Tie receptors (Tie-1 and Tie-2) in placentas from pregnancies complicated by placenta accreta. STUDY DESIGN: Paraffin sections of 46 placental specimens with (cases) and 46 without (controls) placenta accreta were studied immunohistochemically for the expression of Tie receptors and angiopoietin-2 in trophoblast populations. Protein levels of Tie receptors and angiopoietins were also examined by Western blot analysis and/or enzyme-linked immunosorbent assay. Controls were matched for gestational age in this case-control study. RESULTS: In both second and third trimesters, the percentage of intermediate/strong immunoreactivity of Tie-2 in the syncytiotrophoblast was significantly lower in cases than controls (P = .015 and .025, respectively). However, Tie-2 expression in the cytotrophoblastic and extravillous trophoblastic cells and Tie-1 in all trophoblast subpopulations were not significantly different between cases and controls (P > .05). The majority of Tie-2 expression, as demonstrated by Western blots, was consistent with the trends of immunohistochemical findings in the syncytiotrophoblast. Enzyme-linked immunosorbent assay in the placental lysates showed that women with placenta accreta demonstrated significantly higher angiopoietin-2 and lower Tie-2 concentrations than did women with normal pregnancies (P = .026 and .003, respectively). Placental angiopoietin-1 levels did not have any significance (P > .05). Also, angiopoietin-2 immunoreactivity in the syncytiotrophoblast was compatible with the finding demonstrated by enzyme-linked immunosorbent assay (P = .005 and .012, respectively). CONCLUSION: These observations suggest that the participation of up-regulated angiopoietin-2 and down-regulated Tie-2 in the placental tissues may indicate a role for these angiogenic factors in the development of placenta accreta.

Angiopoietin-1↗

PubMed2006

Interaction between Tie receptors modulates angiogenic activity of angiopoietin2 in endothelial progenitor cells.

OBJECTIVE: Ischemia-dependent upregulation of angiopoietin2 (Ang2) led us to hypothesize the potentially proangiogenic Ang2-Tie2 signaling in endothelial progenitor cells (EPCs). Given the well-known vascular destabilizing action of Ang2 in mature endothelium, we investigated the yet unidentified mechanism behind cell-dependent differential activity of Ang2. METHODS AND RESULTS: Both in vitro and in vivo experiments showed that Ang2 promoted angiogenicity of human cord blood-derived EPCs, where Ang2 directly activated Tie2 and its related downstream signaling molecules. However, Ang2 had no such effect in fully differentiated human umbilical vein endothelial cells (HUVECs) under the same condition. Such a cell-dependent Tie2 activation by Ang2 was explained by comparing EPCs and HUVECs, where most Tie2 receptors in EPCs were found to be present unbound to Tie1, whereas those in HUVECs existed as heterocomplexes with Tie1. When Tie2 in HUVECs was prevented from forming heterocomplexes by silencing Tie1 expression, they underwent rapid phosphorylation upon Ang2 treatment, as shown in EPCs. CONCLUSIONS: In contrast with its roles in mature endothelial cells, Ang2 has proangiogenic activities in EPC directly through Tie2 signaling pathway. Such a cell-dependent differential reactivity of Ang2 was for the first time found to be modulated by physical association between Tie1 and Tie2, which inhibited Ang2-mediated Tie2 activation.

Angiopoietin-2↗

PubMed1994

The mouse tie receptor tyrosine kinase gene: expression during embryonic angiogenesis.

Angiogenesis, the process by which new blood vessels are formed, is essential in reproduction, development, wound repair and oncogenesis. Endothelial receptor tyrosine kinases are likely to play key roles in the intercellular signalling controlling angiogenesis. We have here analysed the expression of the endothelial receptor tyrosine kinase tie during the earliest stages of vascular development. The mouse tie cDNA was isolated and sequenced and the exon structure of the coding region was determined. The part of the tie gene encoding the extracellular domain was found to be organized in exons specifying the characteristic domains of the Tie polypeptide. Early postimplantation mouse tissues were analysed for tie expression by in situ hybridization. No tie mRNA was detected in 7.5 day mouse embryos. In 8.5 day embryos, tie expression was observed in differentiating angioblasts of the head mesenchyme, in the splanchnopleure and dorsal aorta as well as in migrating endothelial cells of the developing heart. A weak tie signal was also obtained from angioblasts in the blood islands of the yolk sac. Furthermore, tie mRNA was prominent in the endocardium of the embryo and in the endothelial cells forming the lung vasculature. Expression of tie persisted in the lung capillaries of adult mice, but was decreased in the endocardium. These results suggest that the tie receptor tyrosine kinase is involved in angiogenesis and/or maintenance of endothelial cell functions.

Amino Acid Sequence↗

PubMed1998

Endothelial tie receptor antigen in maternal and cord blood of healthy and preeclamptic subjects.

OBJECTIVE: To measure the vascular endothelial receptor tyrosine kinase Tie, essential in the process of angiogenesis, in blood from healthy and preeclamptic pregnant women, in umbilical cord blood from both, and in blood from nonpregnant women. METHODS: A total of 143 women participated in four arms of the study. Blood samples were collected from 54 healthy nonlaboring pregnant women (gestational weeks 14-41). Samples were collected immediately prepartum and postpartum from another 40 healthy women (15 delivered vaginally and 25 by cesarean) and 15 preeclamptic women (all delivered by cesarean). Arterial and venous cord samples were collected, when possible, from infants born by cesarean. Single blood samples were drawn from 34 nonpregnant controls. Of these, weekly samples from 11 were drawn during one menstrual cycle. A time-resolved fluoroimmunoassay was developed for the detection of the soluble extracellular domain of Tie. RESULTS: Maternal serum Tie levels decreased with advancing gestational age after 26 weeks (r = .6, P < .001). They were significantly higher in healthy women at term (median 233 ng/mL, range 152-414 ng/mL) compared with nonpregnant controls (median 173 ng/mL, range 107-333 ng/mL, P < .001) or with preeclamptic women at term (median 152 ng/mL, range 90-372 ng/mL, P < .05). This difference between healthy and preeclamptic women persisted on the first postpartum day (median 221 ng/mL, range 128-343 and median 152 ng/mL, range 90-372 ng/mL, respectively, P < .05). The highest levels of serum Tie receptor were observed in umbilical arterial and venous blood (median 240 ng/mL, range 174-474 ng/mL and median 340 ng/mL, range 245-690 ng/mL, respectively). In nonpregnant women, serum Tie levels did not vary with menstrual cycle. CONCLUSION: The high levels of the extracellular domain of Tie in healthy term maternal and cord blood may indicate a role for Tie in the vascular development of human fetuses and placentas.

Adult↗

PubMed2002

Differential expression of the angiogenic Tie receptor family in arthritic and normal synovial tissue.

Angiopoietins (Ang) are vascular endothelial cell-specific growth factors that play important roles principally during the later stages of angiogenesis. We have compared the distribution of the receptor tyrosine kinase (Tie) and the Ang ligands in synovial tissues from normal subjects and those with rheumatoid arthritis (RA) and osteoarthritis (OA). Immunohistochemical analysis was used to determine the expression of Ang-1, Ang-2, Tie1 and Tie2 in synovial tissue of normal subjects and those with RA and OA. Ang-1, Ang-2, Tie1 and Tie2 mRNA and protein expression were quantified in synovial tissues and RA synovial tissue fibroblasts with real-time reverse transcription polymerase chain reaction and western blot analysis. In RA, Ang-1 positive immunostaining on lining cells, macrophages and endothelial cells was significantly higher than in OA and normal synovial tissue. The expression pattern of Ang-2 in synovial tissue was similar in RA and OA, whereas the Ang-2 expression was low in normal tissue. Synovial tissue from subjects with RA and OA showed a significant upregulation of Tie1 on lining cells, macrophages and endothelial cells compared to that from normal subjects. Tie2 was significantly upregulated in the RA and OA synovial tissue lining cells, macrophages and smooth muscle cells compared to normal synovial tissue. Generally Ang-1, Ang-2, Tie1 and Tie2 mRNA levels were higher in RA synovial tissue compared to normal and OA synovial tissues, and RA synovial tissue fibroblasts. Western blot analysis also demonstrated greater Tie1 and Tie2 protein expression in RA and OA synovial tissue compared to RA synovial tissue fibroblasts. In conclusion, the dominance of Ang-1 mRNA and protein expression over Ang-2 is in agreement with an active neovascularization in RA synovial tissue.

Angiopoietin-1↗

PubMed2005

Soluble angiopoietin receptor Tie-2 in patients with acute myocardial infarction and its effects on angiogenesis.

Tie-2 receptor has been shown to play a role in the neovascularization of tumors, but little is known about the role it may play in acute myocardial infarction (AMI). The aims of this research are (1) To study the variety of soluble Tie-2 (sTie-2) in patients with AMI. (2) To study the effects of recombinant soluble Tie-2/Fc on HUVECs viability and tube formation in vitro. Serum levels of sTie-2 in 27 patients with AMI were measured on admission (day 1), day 2, day 3 and day 7 after onset of chest pain and 28 healthy controls by ELISA. In addition, the viability of HUVECs and tube formation area were measured after stimulated with recombinant Tie-2/Fc chimera. Median level of sTie-2 increased significantly in the AMI patients when compared with the controls and the maximum level appeared at day 2 after onset of AMI. Tie-2/Fc induced EC apoptosis and inhibited HUVEC tube formation in vitro. Results of this study showed that the level of sTie-2 increased in AMI. The effects of Tie-2/Fc on EC viability and tube formation indicated that angiogenesis might be inhibited in the acute phase of AMI.

Aged↗

PubMed2004

Plasma vascular endothelial growth factor, angiopoietin-2, and soluble angiopoietin receptor tie-2 in diabetic retinopathy: effects of laser photocoagulation and angiotensin receptor blockade.

BACKGROUND: Proliferative diabetic retinopathy (PDR) may be a response to abnormal angiogenic growth factors such as vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), and the soluble angiopoietin receptor tie-2. The authors hypothesised the following: (a) there are differences in plasma levels of these growth factors in different grades of diabetic retinopathy; and (b) that the effects of intervention with panretinal laser photocoagulation (PRP) for PDR, and angiotensin receptor blockade (using eprosartan) for patients with other grades of diabetic retinopathy will be to reduce levels of the growth factors. METHODS: Cross sectional and interventional study (using PRP and eprosartan) in diabetic patients. VEGF, Ang-2, and tie-2 were measured by ELISA. RESULTS: VEGF (p<0.001) and Ang-2 levels (p<0.001) were significantly higher in 93 diabetic patients compared to 20 healthy controls, with the highest levels in grade 2 and grade 3 diabetic retinopathy (p<0.05). Tie-2 was lower in diabetics compared to controls (p = 0.008), with no significant differences between the diabetic subgroups. Overall, VEGF significantly correlated with Ang-2 (p<0.001) and tie-2 (p = 0.004) but the correlation between Ang-2 and tie-2 levels was not significant (p = 0.065). Among diabetic patients only, VEGF levels were significantly correlated with Ang-2 (p<0.001) and tie-2 (p<0.001); the correlation between Ang-2 and tie-2 levels was also significant (p<0.001). There were no statistically significant effects of laser photocoagulation on plasma VEGF, Ang-2, and tie-2 in the 19 patients with PDR, or any effects of eprosartan in the 28 patients with non-proliferative diabetic retinopathy. CONCLUSION: Increased plasma levels of VEGF and Ang-2, as well as lower soluble tie-2, were found in diabetic patients. The highest VEGF and Ang-2 levels were seen among patients with pre-proliferative and proliferative retinopathy, but there was no relation of tie-2 to the severity of retinopathy. As the majority of previous research into Ang-2 and tie-2 has been in relation to angiogenesis and malignancy, the present study would suggest that Ang-2 and tie-2 may be used as potential indices of angiogenesis in diabetes mellitus (in addition to VEGF) and may help elucidate the role of the angiopoietin/tie-2 system in this condition.

Acrylates↗

PubMed2003

Role of Angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphangiogenesis.

This review focuses on the signaling system involving the Angiopoietin1/Tie2 receptor, which appears to be involved in the secondary stages of blood vessel formation. Although this system is crucial for blood and lymphatic vessel formation, identifying its precise role in embryonic and adult vascular biology has been a major challenge. The evidence for the key role of the Angiopoietin/Tie system is discussed, and some of the other members of the system (Ang2, Tie1) are mentioned. A comparison is made with the VEGF signaling system, which seems to provide a complementary, and somewhat more tractable, signaling system. Some of the basic unanswered questions concerning Tie/Angiopoietin biology and the secondary stages of blood vessel formation are also highlighted.

Angiopoietins↗

PubMed1997

Regulation of tie receptor expression on human endothelial cells by protein kinase C-mediated release of soluble tie.

The expression and activity of receptor tyrosine kinases (RTK) at the cell surface can be modulated by several different pathways including the proteolytic release of the extracellular domain as a soluble receptor. We investigated the regulation of tie receptor expression, an orphan RTK restricted to cells of hematopoietic and endothelial lineages, on primary human endothelial cells and a stably transfected Chinese hamster ovary (CHO) cell line. Tie was expressed in cells as a doublet of 135 and 125 kD; the 135-kD band represented mature cell surface receptor containing sialic acid and N-linked oligosaccharide residues, whereas the 125-kD band represented an intracellular pool of immature receptor. Phorbol 12-myristate 13-acetate (PMA) had dramatic effects on tie expression at the cell surface. Within 15 minutes of PMA treatment, the 135-kD band disappeared from the cell surface and was accompanied by the appearance of a 100-kD band in cell supernatants. The 100-kD band continued to accumulate in the media throughout the duration of PMA treatment during which mature tie receptor was undetectable on the cell surface by fluorescence-activated cell sorting (FACS) or in cell lysates by immunoblot analysis. Using specific antibodies, this 100-kD species was shown to be a soluble form of the tie receptor containing the extracellular domain. PMA-dependent release of soluble tie was mediated through the activation of protein kinase C (PKC); soluble tie was not released in the presence of PKC inhibitors, an inactive PMA analog, or following the downregulation of PKC through chronic PMA treatment. These results indicate that tie receptor expression on endothelial cells is regulated by the release of a soluble extracellular fragment following activation of PKC. Parallel pathways regulating c-kit, tumor necrosis factor (TNF), and colony-stimulating factor (CSF) receptor expression suggest that the release of extracellular receptor fragments represents an alternative mechanism through which cells modulate responses to growth factors and cytokines.

Animals↗

PubMed2006

Structure of the extracellular domain of Tie receptor tyrosine kinases and localization of the angiopoietin-binding epitope.

Angiogenesis is essential for tissue repair and regeneration during wound healing but also plays important roles in many pathological processes including tumor growth and metastasis. The receptor protein tyrosine kinase Tie2 and its ligands, the angiopoietins, have important functions in the regulation of angiogenesis. Here, we report a detailed structural and functional characterization of the extracellular region of Tie2. Sequence analysis of the extracellular domain revealed an additional immunoglobulin-like domain resulting in a tandem repeat of immunoglobulin-like domains at the N terminus of the protein. The same domain organization was also found for the Tie1 receptor that shares a high degree of homology with Tie2. Based on structural similarities to other receptor tyrosine kinases and cell adhesion molecules, we demonstrate that the N-terminal two immunoglobulin-like domains of Tie2 harbor the angiopoietin-binding site. Using transmission electron microscopy we furthermore show that the extracellular domain of Tie receptors consists of a globular head domain and a short rod-like stalk that probably forms a spacer between the cell surface and the angiopoietin-binding site. Mutational analysis demonstrated that the head domain consists of the three immunoglobulin-like domains and the three epidermal growth factor-like modules and that the stalk is formed by the three fibronectin type III repeats. These findings might be of particular interest for drug development because Tie receptors are potential targets for treatment of angiogenesis-associated diseases.

Angiopoietin-1↗

PubMed2004

Expression and function of the angiopoietin receptor Tie-2 in human eosinophils.

BACKGROUND: Increased vascularity of bronchial mucosa is closely related to the expression of angiogenic factors, which contribute to the pathogenesis of diseases such as asthma bronchiale. OBJECTIVE: Here we examine the effects of the angiogenic growth factors angiopoietin 1 and angiopoietin 2 on eosinophil function in vitro and possible involvement of the angiopoietin receptor Tie-2. METHODS: Eosinophil migration was studied by micropore filter assays. Signaling mechanisms required for angiopoietin-dependent migration were tested by using signaling enzyme blockers. Tie-2 mRNA and receptor expression on the cell surface of eosinophils was demonstrated in RT-PCR and by fluorescence-activated cell sorting analysis. RESULTS: Angiopoietin 1 significantly stimulated eosinophil chemotaxis via activation of phosphodiesterase, phosphatidylinositol 3'-kinase, and tyrosine kinases. The effect on eosinophil migration of angiopoietin 1 was reversed by an antibody against the Tie-2 receptor and by angiopoietin 2. Incubation of eosinophils with angiopoietin 1 abolished the chemotactic effects of vascular endothelial growth factor on human eosinophils via the Tie-2 receptor. Finally, Tie-2 expression by human eosinophils was demonstrated on the transcriptional and protein level. CONCLUSIONS: Data suggest that angiopoietin 1 stimulates directed migration and possibly inhibits vascular endothelial growth factor-induced eosinophil chemotaxis via its Tie-2 receptor, which is expressed by eosinophils. Thus, angiopoietin 1 may play an important role in the modulation of eosinophilic inflammation.

1-Methyl-3-isobutylxanthine↗