Loss of fibulin-5 binding to β1 integrins inhibits tumor growth by increasing the level of ROS

Schluterman, Marie K.; Chapman, Shelby L.; Korpanty, Grzegorz; Ozumi, Kiyoshi; Fukai, Tohru; Yanagisawa, Hiromi; Brekken, Rolf A.

doi:10.1242/dmm.003707

Cited by 55 publications

(40 citation statements)

References 40 publications

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“…The mechanisms underlying the prosurvival properties of FBLN5 remain complex and not well understood. Recently, it has been described that FBLN5 regulates reactive oxygen species production in endothelial cells (50). Furthermore, FBLN5 is able to activate integrin signaling, involved in cell survival (57,58), although, as we mentioned above, in some scenarios, it has been postulated as an integrin antagonist.…”

Section: Discussionmentioning

confidence: 90%

“…In addition, mutations in the FBLN5 gene are related with macular degeneration and severe forms of cutis laxa (44,45). Interestingly, FBLN5 acts as a multifunctional protein involved in cell-cell and matrix-cell signaling pathways key for vascular cell proliferation, adhesion, and migration (11, 15, 17, 46 -48), as well as for vascular redox state (49,50) and synthesis of ECM proteases (51,52). Our current work demonstrates that hypoxic stress induces FBLN5 expression in vascular endothelial cells (human, bovine, or mouse endothelial cells), an effect that is extensive to other cell types.…”

Section: Discussionmentioning

confidence: 99%

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Fibulin-5 Is Up-regulated by Hypoxia in Endothelial Cells through a Hypoxia-inducible Factor-1 (HIF-1α)-dependent Mechanism

Guadall¹,

Orriols

Rodríguez-Calvo³

et al. 2011

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Fibulin-5 Is Up-regulated by Hypoxia in Endothelial Cells through a Hypoxia-inducible Factor-1 (HIF-1α)-dependent Mechanism

Guadall¹,

Orriols

Rodríguez-Calvo³

et al. 2011

Journal of Biological Chemistry

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“…However, fibulin-5 fails to activate downstream signalling after binding to α 5 β 1 and α 4 β 1 integrins, suggesting that fibulin-5 may act in a dominant-negative fashion to inhibit fibronectin receptor-mediated signalling. On the other hand, loss of fibulin-5 binding to β 1-integrins prevents pancreatic tumour growth by increasing the levels of ROS (reactive oxygen species) [49]. These results suggest that readouts of the cross-talk between fibulin-5 and different subsets of integrins are cell-type-and context-specific.…”

Section: Discussionmentioning

confidence: 99%

Fibulin-5 binds urokinase-type plasminogen activator and mediates urokinase-stimulated β1-integrin-dependent cell migration

Kapustin

Stepanova

Aniol

et al. 2012

Biochemical Journal

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uPA (urokinase-type plasminogen activator) stimulates cell migration through multiple pathways, including formation of plasmin and extracellular metalloproteinases, and binding to the uPAR (uPA receptor; also known as CD87), integrins and LRP1 (low-density lipoprotein receptor-related protein 1) which activate intracellular signalling pathways. In the present paper we report that uPA-mediated cell migration requires an interaction with fibulin-5. uPA stimulates migration of wild-type MEFs (mouse embryonic fibroblasts) (Fbln5+/+ MEFs), but has no effect on fibulin-5-deficient (Fbln5−/−) MEFs. Migration of MEFs in response to uPA requires an interaction of fibulin-5 with integrins, as MEFs expressing a mutant fibulin-5 incapable of binding integrins (FblnRGE/RGE MEFs) do not migrate in response to uPA. Moreover, a blocking anti-(human β1-integrin) antibody inhibited the migration of PASMCs (pulmonary arterial smooth muscle cells) in response to uPA. Binding of uPA to fibulin-5 generates plasmin, which excises the integrin-binding N-terminal cbEGF (Ca2+ -binding epidermal growth factor)-like domain, leading to loss of β1-integrin binding. We suggest that uPA promotes cell migration by binding to fibulin-5, initiating its cleavage by plasmin, which leads to its dissociation from β1-integrin and thereby unblocks the capacity of integrin to facilitate cell motility.

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“…Direct evidence has been reported linking FBLN 5 to angiogenesis and regarding FBLN 5 as an endogenous inhibitor of angiogenesis and endothelial cell activities [22,24]. VEGF, a key regulator of vascu logenesis and angiogenesis, dramatically down regu lates FBLN 5 expression, suggesting that reduced FBLN 5 expression is necessary for angiogenesis acti vation [11].…”

Section: Fbln 5 and Angiogenesismentioning

confidence: 99%

“…In endothelial cells, FBLN 5 expression prevents the activation of ERK1/2 and p38 MAPK, but promotes angiogenesis resolution by targeting TSP 1, a natural inhibitor of neovascularization and tumorigenesis [11]. FBLN 5 binds to β1 integrins to activate integrin induced ROS production, representing the underlying cause for the reduction in angiogenesis and tumor growth [24]. On the other hand, FBLN 5 antagonizes fibronectin induced stress fiber formation and focal adhesion in smooth muscle cell by binding to α5β1 and α4β inte grins, but fails to activate downstream signaling [13], suggesting that FBLN 5 acts in a dominant negative role to inhibit fibronectin receptor mediated signal ing.…”

Section: Fbln 5 and Angiogenesismentioning

confidence: 99%

Diverse functions of fibulin-5 in tumor

2014

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The extracellular matrix (ECM) is composed of structural proteins, glycosaminoglycans, growth fac tors, cytokines, and glycoproteins (also called matri cellular proteins). It provides structural support and directly affects cell behavior, including adhesion, migration, proliferation and survival [1]. Moreover, matricellular proteins participate in matrix cell inter actions and exert regulatory roles via a variety of molecular mechanisms [2]. Although an increasing number of ECM proteins have emerged as matricellu lar proteins, it is still difficult to accurately draw a line between structural proteins and matricellular proteins. The fibulin family of ECM proteins is essential for the formation of elastic fibers and basement membranes, and plays diverse cellular and biological functions both in matrix and neighboring cells [3], which are suppos edly included as part of the matricellular family.Fibulin 5 (FBLN 5; also known as DANCE or EVEC) is a member of Class II short fibulins and has molecular weight of 66Kda. This matricellular pro tein, identified by two research groups in an attempt to isolate a novel regulator of vascular growth, is expressed in elastin rich tissues, such as aorta, kidney, lung, uterus, adult heart, ovary and colon [4,5], and functions as a mediator of cell cell and cell matrix communications. Moreover, FBLN 5 is an endoge nous angiogenesis inhibitor and is associated with the development of cutis laxa (a genetically heritable dis order) or age related macular degeneration. Although the roles of FBLN 5 in tumorigenesis remain to be fully elucidated, recent research has revealed that FBLN 5 regulates cancer cell proliferation, migration and invasion in a cell and context specific manner. FBLN 5 has reduced expression in certain metastatic human tumors such as lung cancer and prostate cancer [6,7], but is overexpressed in fibrosarcoma and nasopharyngeal carcinoma [8,9]. Here, the role of FBLN 5 in regulating cancer cell activities is summa rized, and the potential use of FBLN 5 as a target to prevent the growth and metastasis of human malig nancies is discussed. FBLN 5 STRUCTURE AND MOLECULAR INTERACTIONS FBLN 5, a 448 amino acid protein, belongs to the fibulin family defined by the presence of two structural modules, namely EGF like domain repeats and a unique C terminal fibulin type module [3] (figure).Abstract-Altered interactions between the extracellular matrix and cells play an important part in tumori genesis and metastasis. As a member of a matricellular glycoprotein, fibulin 5 is expressed in elastin rich tis sues and organizes the matrix structures by interacting with many extracellular proteins. Fibulin 5 expression is closely associated with normal embryonic development and organogenesis. Mice deficient for the fibulin 5 gene exhibit systemic elastic fiber defects with manifestation of loose skin, emphysematous lungs and tortu ous vessels. Additionally, fibulin 5 null mice exhibited increased angiogenesis after wound healing or PVA sponge implantation and matrigel implantation exp...

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Loss of fibulin-5 binding to β1 integrins inhibits tumor growth by increasing the level of ROS

Cited by 55 publications

References 40 publications

Fibulin-5 Is Up-regulated by Hypoxia in Endothelial Cells through a Hypoxia-inducible Factor-1 (HIF-1α)-dependent Mechanism

Fibulin-5 Is Up-regulated by Hypoxia in Endothelial Cells through a Hypoxia-inducible Factor-1 (HIF-1α)-dependent Mechanism

Fibulin-5 binds urokinase-type plasminogen activator and mediates urokinase-stimulated β1-integrin-dependent cell migration

Diverse functions of fibulin-5 in tumor

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