The Lysyl Oxidase Pro-peptide Attenuates Fibronectin-mediated Activation of Focal Adhesion Kinase and p130Cas in Breast Cancer Cells

Zhao, Yong; Min, Chengyin; Vora, Siddharth R.; Trackman, Philip C.; Sonenshein, Gail E.; Kirsch, Kathrin H.

doi:10.1074/jbc.m802612200

Cited by 61 publications

(36 citation statements)

References 41 publications

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“…In vascular smooth muscle cells, tumor necrosis factor-␣ signaling is inhibited (38), although in breast cancer cells RAS-dependent pathways and FAK activation and haptotaxis are inhibited (63). Taken together, these findings suggest that LOX-PP has more than one molecular target and mechanism of action.…”

Section: Discussionmentioning

confidence: 56%

Lysyl Oxidase Propeptide Inhibits FGF-2-induced Signaling and Proliferation of Osteoblasts

Vora

Palamakumbura

Mitsi

et al. 2010

Journal of Biological Chemistry

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Pro-lysyl oxidase is secreted as a 50-kDa proenzyme and is then cleaved to a 30-kDa mature enzyme (lysyl oxidase (LOX)) and an 18-kDa propeptide (lysyl oxidase propeptide (LOX-PP)). The presence of LOX-PP in the cell layers of phenotypically normal osteoblast cultures led us to investigate the effects of LOX-PP on osteoblast differentiation. Data indicate that LOX-PP inhibits terminal mineralization in primary calvaria osteoblast cultures when added at early stages of differentiation, with no effects seen when present at later stages. LOX-PP was found to inhibit serum-and FGF-2-stimulated DNA synthesis and FGF-2-stimulated cell growth. Enzyme-linked immunosorbent assay and Western blot analyses show that LOX-PP inhibits FGF-2-induced ERK1/2 phosphorylation, signaling events that mediate the FGF-2-induced proliferative response. LOX-PP inhibits FGF-2-stimulated phosphorylation of FRS2␣ and FGF-2-stimulated DNA synthesis, even after inhibition of sulfation of heparan sulfate proteoglycans. These data point to a LOX-PP target at or near the level of fibroblast growth factor receptor binding or activation. Ligand binding assays on osteoblast cell layers with 125 I-FGF-2 demonstrate a concentration-dependent inhibition of FGF-2 binding to osteoblasts by LOX-PP. In vitro binding assays with recombinant fibroblast growth factor receptor protein revealed that LOX-PP inhibits FGF-2 binding in an uncompetitive manner. We propose a working model for the respective roles of LOX enzyme and LOX-PP in osteoblast phenotype development in which LOX-PP may act to inhibit the proliferative response possibly to allow cells to exit from the cell cycle and progress to the next stages of differentiation.The process of bone formation is highly coordinated and has been divided into three identifiable stages as follows: proliferation, matrix maturation, and mineralization (1). Tightly controlled expression and action of growth factors and extracellular matrix molecules act in an autocrine and paracrine manner to promote osteoblast development and differentiation (2-4). The fibroblast growth factors (FGFs) 2 are a family of structurally related proteins, with 23 members identified (5). The role of FGF-2 in bone formation is highlighted by genetic studies in which overexpression of FGF-2 induces abnormal long bone formation, although its knockdown inhibits bone formation and reduces bone mass (6, 7). Additionally, several mutations in FGF receptors have been implicated in the etiology of human skeletal dysplasias (5, 8). FGF-2 is a key mitogen for various types of bone cells, including precursor cells, bone marrow stromal cells, calvarial osteoblasts, and mature osteoblasts (9 -12). FGF-2 contributes to the expansion of the pool of cells during the proliferative phase (9, 11, 13). Its role in the later stages of matrix maturation and mineralization is, however, controversial, with both positive (14 -17) and negative effects described (18 -21). Similar to effects of other mitogenic growth factors (22-25), chronic in vitro exposure of oste...

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Section: Discussionmentioning

confidence: 56%

Lysyl Oxidase Propeptide Inhibits FGF-2-induced Signaling and Proliferation of Osteoblasts

Vora

Palamakumbura

Mitsi

et al. 2010

Journal of Biological Chemistry

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“…Although it has been widely accepted that mature active LOX functions in the extracellular cross‐linking of collagens and elastin, this active form of LOX has also been detected to be increased inside the VSMCs and is able to stimulate intracellular signaling pathways as detected in LOX transgenic mice (Martinez‐Revelles et al., 2017). In addition, it has been reported that LOX‐PP participates in the regulation of the focal adhesion kinase in cancer cells (Zhao et al., 2009), although its biological activity in VSMC remains to be identified. These observations suggest the existence of undefined roles of M‐LOX and LOX‐PP in the cellular function of VSMCs via intracellular effects, which may also involve the regulation of aortic stiffness.…”

Section: Discussionmentioning

confidence: 99%

Vascular smooth muscle cells direct extracellular dysregulation in aortic stiffening of hypertensive rats

Hays

Zhou

et al. 2018

Aging Cell

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SummaryAortic stiffening is an independent risk factor that underlies cardiovascular morbidity in the elderly. We have previously shown that intrinsic mechanical properties of vascular smooth muscle cells (VSMCs) play a key role in aortic stiffening in both aging and hypertension. Here, we test the hypothesis that VSMCs also contribute to aortic stiffening through their extracellular effects. Aortic stiffening was confirmed in spontaneously hypertensive rats (SHRs) vs. Wistar‐Kyoto (WKY) rats in vivo by echocardiography and ex vivo by isometric force measurements in isolated de‐endothelized aortic vessel segments. Vascular smooth muscle cells were isolated from thoracic aorta and embedded in a collagen I matrix in an in vitro 3D model to form reconstituted vessels. Reconstituted vessel segments made with SHR VSMCs were significantly stiffer than vessels made with WKY VSMCs. SHR VSMCs in the reconstituted vessels exhibited different morphologies and diminished adaptability to stretch compared to WKY VSMCs, implying dual effects on both static and dynamic stiffness. SHR VSMCs increased the synthesis of collagen and induced collagen fibril disorganization in reconstituted vessels. Mechanistically, compared to WKY VSMCs, SHR VSMCs exhibited an increase in the levels of active integrin β1‐ and bone morphogenetic protein 1 (BMP1)‐mediated proteolytic cleavage of lysyl oxidase (LOX). These VSMC‐induced alterations in the SHR were attenuated by an inhibitor of serum response factor (SRF)/myocardin. Therefore, SHR VSMCs exhibit extracellular dysregulation through modulating integrin β1 and BMP1/LOX via SRF/myocardin signaling in aortic stiffening.

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“…In H1299 lung cancer cells, which contain a mutant NRAS gene, LOX-PP reduced the activation of ERK and Akt, and ability for anchorage-independent growth and invasive colony formation in Matrigel [25]. LOX-PP also attenuated fibronectin-mediated activation of focal adhesion kinase in breast cancer cells [34], [35], and fibroblast growth factor (FGF)-2-induced proliferation of prostate cancer cells [36]. Here we asked whether Blimp1 is expressed in lung cancer cells given the important role of Ras signaling in these cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Blimp1 Activation by AP-1 in Human Lung Cancer Cells Promotes a Migratory Phenotype and Is Inhibited by the Lysyl Oxidase Propeptide

Sato

Trackman

et al. 2012

PLoS ONE

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B lymphocyte-induced maturation protein 1 (Blimp1) is a master regulator of B cell differentiation, and controls migration of primordial germ cells. Recently we observed aberrant Blimp1 expression in breast cancer cells resulting from an NF-κB RelB to Ras signaling pathway. In order to address the question of whether the unexpected expression of Blimp1 is seen in other epithelial-derived tumors, we selected lung cancers as they are frequently driven by Ras signaling. Blimp1 was detected in all five lung cancer cell lines examined and shown to promote lung cancer cell migration and invasion. Interrogation of microarray datasets demonstrated elevated BLIMP1 RNA expression in lung adenocarcinoma, pancreatic ductal carcinomas, head and neck tumors as well as in glioblastomas. Involvement of Ras and its downstream kinase c-Raf was confirmed using mutant and siRNA strategies. We next addressed the issue of mechanism of Blimp1 activation in lung cancer. Using knockdown and ectopic expression, the role of the Activator Protein (AP)-1 family of transcription factors was demonstrated. Further, chromatin immunoprecipitation assays confirmed binding to identified AP-1 elements in the BLIMP1 promoter of ectopically expressed c-Jun and of endogenous AP-1 subunits following serum stimulation. The propeptide domain of lysyl oxidase (LOX-PP) was identified as a tumor suppressor, with ability to reduce Ras signaling in lung cancer cells. LOX-PP reduced expression of Blimp1 by binding to c-Raf and inhibiting activation of AP-1, thereby attenuating the migratory phenotype of lung cancer cells. Thus, Blimp1 is a mediator of Ras/Raf/AP-1 signaling that promotes cell migration, and is repressed by LOX-PP in lung cancer.

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The Lysyl Oxidase Pro-peptide Attenuates Fibronectin-mediated Activation of Focal Adhesion Kinase and p130Cas in Breast Cancer Cells

Cited by 61 publications

References 41 publications

Lysyl Oxidase Propeptide Inhibits FGF-2-induced Signaling and Proliferation of Osteoblasts

Lysyl Oxidase Propeptide Inhibits FGF-2-induced Signaling and Proliferation of Osteoblasts

Vascular smooth muscle cells direct extracellular dysregulation in aortic stiffening of hypertensive rats

Blimp1 Activation by AP-1 in Human Lung Cancer Cells Promotes a Migratory Phenotype and Is Inhibited by the Lysyl Oxidase Propeptide

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