Cellular and molecular mechanisms of HGF/Met in the cardiovascular system

Met tyrosine kinase receptor, also known as c-Met, is the HGF (hepatocyte growth factor) receptor. The HGF/Met pathway has a prominent role in cardiovascular remodelling after tissue injury. The present review provides a synopsis of the cellular and molecular mechanisms underlying the effects of HGF/Met in the heart and blood vessels. In vivo, HGF/Met function is particularly important for the protection of the heart in response to both acute and chronic insults, including ischaemic injury and doxorubicin-induced cardiotoxicity. Accordingly, conditional deletion of Met in cardiomyocytes results in impaired organ defence against oxidative stress. After ischaemic injury, activation of Met provides strong anti-apoptotic stimuli for cardiomyocytes through PI3K (phosphoinositide 3-kinase)/Akt and MAPK (mitogen-activated protein kinase) cascades. Recently, we found that HGF/Met is also important for autophagy regulation in cardiomyocytes via the mTOR (mammalian target of rapamycin) pathway. HGF/Met induces proliferation and migration of endothelial cells through Rac1 (Ras-related C3 botulinum toxin substrate 1) activation. In fibroblasts, HGF/Met antagonizes the actions of TGFβ1 (transforming growth factor β1) and AngII (angiotensin II), thus preventing fibrosis. Moreover, HGF/Met influences the inflammatory response of macrophages and the immune response of dendritic cells, indicating its protective function against atherosclerotic and autoimmune diseases. The HGF/Met axis also plays an important role in regulating self-renewal and myocardial regeneration through the enhancement of cardiac progenitor cells. HGF/Met has beneficial effects against myocardial infarction and endothelial dysfunction: the cellular and molecular mechanisms underlying repair function in the heart and blood vessels are common and include pro-angiogenic, anti-inflammatory and anti-fibrotic actions. Thus administration of HGF or HGF mimetics may represent a promising therapeutic agent for the treatment of both coronary and peripheral artery disease.

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Regulation of human trophoblast migration and invasiveness

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y02-016 ◽

2002 ◽

Vol 80 (2) ◽

pp. 116-124 ◽

Cited By ~ 146

Author(s):

Chandan Chakraborty ◽

Louise M Gleeson ◽

Timothy McKinnon ◽

Peeyush K Lala

Keyword(s):

Cell Migration ◽

Growth Factor ◽

Plasminogen Activator ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Mitogen Activated Protein Kinase ◽

Extravillous Trophoblast ◽

Type I ◽

Human Trophoblast ◽

Trophoblast Migration

The human placenta is an invasive structure in which highly proliferative, migratory, and invasive extravillous trophoblast (EVT) cells migrate and invade the uterus and its vasculature. Using in vitro propagated normal first-trimester EVT cells and immortalized EVT cells, which share all of the phenotypic and functional characteristics of the normal EVT cells, it has been shown that migration/invasion of human EVT cells is stringently regulated by many growth factors, their binding proteins, extracellular matrix (ECM) components, and some adhesion molecules in an autocrine/paracrine manner at the fetalmaternal interface in human pregnancy. Transforming growth factor β (TGF-β), decorin (a proteoglycan in the ECM), and melanoma cell adhesion molecule (Mel-CAM) inhibit, and insulin-like growth factor II (IGF-II), IGF-binding protein 1 (IGFBP-1), and endothelin 1 (ET-1) stimulate EVT cell migration/invasion. Inhibition of EVT cell migration by TGF-β has been suggested to be due to upregulation of integrins, which make the cells more adhesive to the ECM. Its antiinvasive action is due to an upregulation of tissue inhibitor of matrix metalloprotease 1 (TIMP-1) and plasminogen activator inhibitor (PAI-1) and a downregulation of urokinase-type plasminogen activator (uPA). Molecular mechanisms of inhibition of migration/invasion of EVT cells by decorin and Mel-CAM remain to be identified. IGF-II action has been shown to be mediated by IGF type I receptors (IGF-RII) independently of IGF type I receptors (IGF-RI) and IGFBPs. This action of IGF-II appears to involve inhibitory G proteins and phosphorylation of mitogen-activated protein kinase (MAPK) (extracellular signal-regulated protein kinases 1 and 2 (ERK-1 and ERK-2)). IGFBP-1 stimulation of EVT cell migration appears to occur by binding its Arg-Gly-Asp (RGD) domain to α5β1 integrin, leading to phosphorylation of focal adhesion kinase (FAK) and MAPK (ERK-1 and ERK-2). These studies may improve our understanding of diseases related to abnormal placentation, viz. hypoinvasiveness in preeclampsia and hyperinvasiveness in trophoblastic neoplasms.Key words: trophoblast, migration, integrin, IGF-RII, IGFBP-1.

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Transforming Growth Factor-β Signal Transduction and Progressive Renal Disease1

Experimental Biology and Medicine ◽

10.1177/153537020222701102 ◽

2002 ◽

Vol 227 (11) ◽

pp. 943-956 ◽

Cited By ~ 81

Author(s):

Jingfei Cheng ◽

Joseph P. Grande

Keyword(s):

Extracellular Matrix ◽

Growth Factor ◽

Dna Sequences ◽

Transforming Growth Factor ◽

Tissue Injury ◽

Transforming Growth Factor Β ◽

Mitogen Activated Protein Kinase ◽

Receptor Complex ◽

Signaling Systems ◽

Mitogen Activated Protein

Transforming growth factor-β (TGF-β) superfamily members are multifunctional growth factors that play pivotal roles in development and tissue homeostasis. Recent studies have underscored the importance of TGF-β in regulation of cell proliferation and extracellular matrix synthesis and deposition. TGF-β signaling is initiated by ligand binding to a membrane-associated receptor complex that has serine/threonine kinase activity. This receptor complex phosphorylates specific Smad proteins, which then transduce the ligand-activated signal to the nucleus. Smad complexes regulate target gene transcription either by directly binding DNA sequences, or by complexing with other transcription factors or co-activators. There is extensive crosstalk between the TGF-β signaling pathway and other signaling systems, including the mitogen-activated protein kinase pathways. The importance of TGF-β in regulation of cell growth has been emphasized by recent observations that mutations of critical elements of the TGF-β signaling system are associated with tumor progression in patients with many different types of epithelial neoplasms. TGF-β has emerged as a predominant mediator of extracellular matrix production and deposition in progressive renal disease and in other forms of chronic tissue injury. In this overview, recent advances in our understanding of TGF-β signaling, cell cycle regulation by TGF-β, and the role of TGF-β in progressive renal injury are highlighted.

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Signaling pathways involved in colorectal cancer progression

Cell & Bioscience ◽

10.1186/s13578-019-0361-4 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 21

Author(s):

Zahra Koveitypour ◽

Farnoush Panahi ◽

Mehrdad Vakilian ◽

Maryam Peymani ◽

Farzad Seyed Forootan ◽

...

Keyword(s):

Colorectal Cancer ◽

Growth Factor ◽

Signaling Pathways ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Growth Factor Receptor ◽

Transforming Growth Factor Β ◽

Mitogen Activated Protein Kinase ◽

Mapk Cascades

AbstractColorectal cancer (CRC) is the fourth leading cause of the worldwide cancer mortality. Different molecular mechanisms have been attributed to the development and progress of CRC. In this review, we will focus on the mitogen-activated protein kinase (MAPK) cascades downstream of the epidermal growth factor receptor (EGFR), Notch, PI3K/AKT pathway, transforming growth factor-β (TGF-β), and Wnt signaling pathways. Various mutations in the components of these signaling pathways have been linked to the development of CRC. Accordingly, numerous efforts have been carried out to target the signaling pathways to develop novel therapeutic approaches. Herein, we review the signaling pathways involved in the incidence and progression of CRC, and the strategies for the therapy targeting components of signaling pathways in CRC.

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Role of the prostaglandin E2/E-prostanoid 2 receptor signalling pathway in TGFβ-induced mice mesangial cell damage

Bioscience Reports ◽

10.1042/bsr20140130 ◽

2014 ◽

Vol 34 (6) ◽

Cited By ~ 3

Author(s):

Na-Na Li ◽

Yu-Yin Xu ◽

Xiao-Lan Chen ◽

Ya-Ping Fan ◽

Jian-Hua Wu

Keyword(s):

Growth Factor ◽

Prostaglandin E2 ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Mesangial Cells ◽

Tissue Growth ◽

Signalling Pathway ◽

Mitogen Activated Protein Kinase ◽

Type I

The prostaglandin E2 receptor, EP2 (E-prostanoid 2), plays an important role in mice glomerular MCs (mesangial cells) damage induced by TGFβ1 (transforming growth factor-β1); however, the molecular mechanisms for this remain unknown. The present study examined the role of the EP2 signalling pathway in TGFβ1-induced MCs proliferation, ECM (extracellular matrix) accumulation and expression of PGES (prostaglandin E2 synthase). We generated primary mice MCs. Results showed MCs proliferation promoted by TGFβ1 were increased; however, the production of cAMP and PGE2 (prostaglandin E2) was decreased. EP2 deficiency in these MCs augmented FN (fibronectin), Col I (collagen type I), COX2 (cyclooxygenase-2), mPGES-1 (membrane-associated prostaglandin E1), CTGF (connective tissue growth factor) and CyclinD1 expression stimulated by TGFβ1. Silencing of EP2 also strengthened TGFβ1-induced p38MAPK (mitogen-activated protein kinase), ERK1/2 (extracellular-signal-regulated kinase 1/2) and CREB1 (cAMP responsive element-binding protein 1) phosphorylation. In contrast, Adenovirus-mediated EP2 overexpression reversed the effects of EP2-siRNA (small interfering RNA). Collectively, the investigation indicates that EP2 may block p38MAPK, ERK1/2 and CREB1 phosphorylation via activation of cAMP production and stimulation of PGE2 through EP2 receptors which prevent TGFβ1-induced MCs damage. Our findings also suggest that pharmacological targeting of EP2 receptors may provide new inroads to antagonize the damage induced by TGFβ1.

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