Betacellulin induces angiogenesis through activation of mitogen‐activated protein kinase and phosphatidylinositol 3’‐kinase in endothelial cells

  title={Betacellulin induces angiogenesis through activation of mitogen‐activated protein kinase and phosphatidylinositol 3’‐kinase in endothelial cells},
  author={Hoe Suk Kim and Hyoung Seek Shin and Hee Jin Kwak and Chung-Hyun Cho and Chin O. Lee and Gou Young Koh},
  journal={The FASEB Journal},
Betacellulin (BTC) is a member of the epidermal growth factor (EGF) family, and it acts through EGF receptors. We asked whether BTC could be an angiogenic factor. Using human umbilical vein endothelial cells (HUVECs), we examined the effect of BTC on kinases and angiogenic processes. BTC induced ERK1/2 and Akt phosphorylation in a dose‐ and time‐dependent manner. BTC induced phosphorylation of all three EGF receptors present on HUVECs: ErbB2, ErbB3, and ErbB4. Pretreatment with effective… 
Angiogenic role of adrenomedullin through activation of Akt, mitogen‐activated protein kinase, and focal adhesion kinase in endothelial cells
  • Won Kim, S. Moon, S. K. Park
  • Biology, Chemistry
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2003
AM exerts angiogenic activity through activation of Akt, MAPK, and focal adhesion kinase in endothelial cells and its effect was inhibited by pretreatment with phosphatidylinositol 3′‐kinase inhibitor or ERK1/2 inhibitor.
Betacellulin and Amphiregulin Induce Upregulation of Cyclin D1 and DNA Synthesis Activity Through Differential Signaling Pathways in Vascular Smooth Muscle Cells
The PI 3′-kinase/Akt/GSK/FoxO/&bgr;-catenin pathway could be the major signaling cascade for BTC-induced upregulation of cyclin D1 protein in HTASMCs, whereas a sustained ERK/Elk1 activation could beThe major signaling cascades for AR-inducedUpregulation ofcyclin D 1 protein inHTAS MCs.
EGFL6 Promotes Endothelial Cell Migration and Angiogenesis through the Activation of Extracellular Signal-regulated Kinase*
It is demonstrated for the first time that osteoblastic-like cells express EGFL6 that is capable of promoting endothelial cell migration and angiogenesis via ERK activation and might offer an important new target for the potential treatment of bone diseases, including osteonecrosis, osteoporosis, and fracture healing.
RANKL regulates endothelial cell survival through the phosphatidylinositol 3′‐kinase/Akt signal transduction pathway
Findings indicate that RANK, in response to the paracrine stimulus of RANKL, may play an important role in maintaining endothelial cell integrity through the PI 3′‐kinase/Akt signal transduction pathway.
EGFL7 Is Expressed in Bone Microenvironment and Promotes Angiogenesis via ERK, STAT3, and Integrin Signaling Cascades
It is shown that recombinant EGFL7 induces phosphorylation of extracellular signal‐regulated kinase 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3), and focal adhesion kinase (FAK) in SVEC cells and regulates endothelial cell activities through integrin‐mediated signaling.
Thrombospondin-1 opens the paracellular pathway in pulmonary microvascular endothelia through EGFR/ErbB2 activation.
It is shown that TSP1 opens the paracellular pathway in human lung microvascular endothelial cells (HMVEC-Ls) in a dose, time, and protein tyrosine kinase (PTK)-dependent manner and disrupts the endothelial barrier through EGFR/ErbB2 activation although additional signals are necessary in cells with low receptor expression.
ErbB Ligands in Angiogenesis
It is shown that EGFR activity is demonstrated to regulate recruitment of bone marrow-derived perivascular cells during tumor neovascularization in vivo and this results indicate that ErbB signaling is involved in the cellular processes of new blood vessel formation.


Utilization of Distinct Signaling Pathways by Receptors for Vascular Endothelial Cell Growth Factor and Other Mitogens in the Induction of Endothelial Cell Proliferation*
Two-hybrid cloning and immunoprecipitation from human umbilical vein endothelial cells (HUVEC) showed that KDR binds to and promotes the tyrosine phosphorylation of phospholipase Cγ (PLCγ), indicating that K DR is uniquely important to PLCγ activation in HUVEC.
Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3'-Kinase/Akt signal transduction pathway.
Findings indicate that the Tie2 receptor, PI 3'-kinase, and Akt are crucial elements in the signal transduction pathway leading to endothelial cell survival induced by the paracrine activity of Ang1.
Epidermal growth factor and betacellulin mediate signal transduction through co‐expressed ErbB2 and ErbB3 receptors
Evidence is provided that ErbB2/ErbB3 binding sites for EGF and BTC are formed by a previously undescribed mechanism that requires co‐expression of two distinct receptors.
Neuregulin activation of ErbB receptors in vascular endothelium leads to angiogenesis.
Marked in vitro and in vivo angiogenic responses to neuregulin-β, which are independent of vascular endothelial cell growth factor, support an important role for the ErbB family of receptors in endothelium cell signaling and function, including neureGulin-induced angiogenesis.
Akt takes center stage in angiogenesis signaling.
It is reported that angiopoietin-1 (Ang1) activates this survival kinase and thereby inhibits endothelial cell apoptosis and seems to be a general antiapoptotic mechanism induced by proangiogenic stimuli.
VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells
Results suggest that in primary endothelial cells, VEGF-induced activation of Raf-MEK-MAP kinase and DNA synthesis are mainly mediated by PKC- dependent pathway, much more than by Ras-dependent or PI3 kinase-dependent pathway.
ErbB2 expression increases the spectrum and potency of ligand-mediated signal transduction through ErbB4.
  • L. M. Wang, A. Kuo, J. Pierce
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1998
The ability of ErbB4 to mediate signal transduction through EGF-like ligands is broader than previously assumed and can be profoundly altered by the concomitant expression of ErBB2.
Vascular endothelial growth factor family members are differentially regulated by c-erbB signaling in head and neck squamous carcinoma cells
The results reveal that the four V EGF genes are regulated by c-erbB signaling pathways in a strikingly different manner, suggesting that they serve distinct, although perhaps complimentary (VEGF-A and VEGF-C) or antagonistic (VE GF-D) functions.
Auto-induction and growth stimulatory effect of betacellulin in human pancreatic cancer cells.
In vivo, in a Panc-1 inoculated athymic mice model, BTC-treated tumors grew approximately five times larger than in control and BTC has thus a significant growth stimulatory effect on pancreatic cancer cells and might function as an autocrine and paracrine growth factor.
Epidermal growth factor receptor transcriptionally up-regulates vascular endothelial growth factor expression in human glioblastoma cells via a pathway involving phosphatidylinositol 3'-kinase and distinct from that induced by hypoxia.
In glioblastoma cells, transcriptional regulation of the VEGF promoter by EGFR appears to involve Ras/PI(3) kinase and to be distinct from signals induced by hypoxia.