CD44 Regulates Hepatocyte Growth Factor-mediated Vascular Integrity

Singleton, Patrick A.; Salgia, Ravi; Moreno‐Vinasco, Liliana; Moitra, Jaideep; Sammani, Saad; Mirzapoiazova, Tamara; Garcia, Joe G.N.

doi:10.1074/jbc.m702573200

Cited by 108 publications

(38 citation statements)

References 73 publications

(100 reference statements)

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“…There is no evidence, to our knowledge, of a direct interaction between Met and NHEs; however, there is evidence that Met may induce NHE activity through a, yet to be defined, tyrosine kinase-calcium/calmodulin-dependent mechanism (Kaneko et al, 1995). In addition, it is possible that CD44, the cell-surface receptor for hyaluronan, is involved, as both Met and NHEs have been shown to interact with CD44 (Bourguignon et al, 2004;Orian-Rousseau et al, 2002;Singleton et al, 2007). It would be interesting to determine if Met, CD44 (specifically the v6 splice variant), and NHEs interact and if the calcium/calmodulin pathway is involved in lysosome trafficking.…”

Section: Discussionmentioning

confidence: 93%

HGF-induced invasion by prostate tumor cells requires anterograde lysosome trafficking and activity of Na+-H+ exchangers

Steffan

Williams

Welbourne

et al. 2010

Journal of Cell Science

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SummaryHepatocyte growth factor (HGF) is found in tumor microenvironments, and interaction with its tyrosine kinase receptor Met triggers cell invasion and metastasis. It was previously shown that acidic extracellular pH stimulated peripheral lysosome trafficking, resulting in increased cathepsin B secretion and tumor cell invasion, which was dependent upon sodium-proton exchanger (NHE) activity. We now demonstrate that HGF induced the trafficking of lysosomes to the cell periphery, independent of HGF-induced epithelialmesenchymal transition. HGF-induced anterograde lysosome trafficking depended upon the PI3K pathway, microtubules and RhoA, resulting in increased cathepsin B secretion and invasion by the cells. HGF-induced NHE activity via increased net acid production, and inhibition of NHE activity with 5-(N-ethyl-N-isopropyl)-amiloride (EIPA), or a combination of the NHE1-specific drug cariporide and the NHE3-specific drug s3226 prevented HGF-induced anterograde trafficking and induced retrograde trafficking in HGFoverexpressing cells. EIPA treatment reduced cathepsin B secretion and HGF-induced invasion by the tumor cells. Lysosomes were located more peripherally in Rab7-shRNA-expressing cells and these cells were more invasive than control cells. Overexpression of the Rab7 effector protein, RILP, resulted in a juxtanuclear location of lysosomes and reduced HGF-induced invasion. Together, these results suggest that the location of lysosomes is an inherently important aspect of invasion by tumor cells.

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Section: Discussionmentioning

confidence: 93%

HGF-induced invasion by prostate tumor cells requires anterograde lysosome trafficking and activity of Na+-H+ exchangers

Steffan

Williams

Welbourne

et al. 2010

Journal of Cell Science

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“…Recent studies show that these cholesterol-enriched detergentresistant membrane microdomains play an important role in formylmethionylleucylphenylalanine-, phorbol myristate acetate-, Fc␥-, and angiotensin II-induced activation of NADPH oxidase by triggering the recruitment of key NADPH oxidase subunits (2,17,18). We have demonstrated that CEMs are critical for Rac1 activation of barrier-enhancing stimuli, including hyaluronan and hepatocyte growth factor (14,15). Hepatocyte growth factor-induced Rac1 activation requires recruitment of the vesicular regulator, dynamin 2, to CEM (15).…”

Section: P40mentioning

confidence: 99%

“…We have demonstrated that CEMs are critical for Rac1 activation of barrier-enhancing stimuli, including hyaluronan and hepatocyte growth factor (14,15). Hepatocyte growth factor-induced Rac1 activation requires recruitment of the vesicular regulator, dynamin 2, to CEM (15). In addition, caveolin-1 is essential for the activation of Rac1 and NADPH oxidase after angiotensin II stimulation of vascular smooth muscle cells (17).…”

Section: P40mentioning

confidence: 99%

Dynamin 2 and c-Abl Are Novel Regulators of Hyperoxia-mediated NADPH Oxidase Activation and Reactive Oxygen Species Production in Caveolin-enriched Microdomains of the Endothelium

Singleton

Pendyala

Горшкова

et al. 2009

Journal of Biological Chemistry

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Reactive oxygen species (ROS) generation, particularly by the endothelial NADPH oxidase family of proteins, plays a major role in the pathophysiology associated with lung inflammation, ischemia/reperfusion injury, sepsis, hyperoxia, and ventilatorassociated lung injury. We examined potential regulators of ROS production and discovered that hyperoxia treatment of human pulmonary artery endothelial cells induced recruitment of the vesicular regulator, dynamin 2, the non-receptor tyrosine kinase, c-Abl, and the NADPH oxidase subunit, p47 phox , to caveolin-enriched microdomains (CEMs). Silencing caveolin-1 (which blocks CEM formation) and/or c-Abl expression with small interference RNA inhibited hyperoxia-mediated tyrosine phosphorylation and association of dynamin 2 with p47 phox and ROS production. In addition, treatment of human pulmonary artery endothelial cells with dynamin 2 small interfering RNA or the dynamin GTPase inhibitor, Dynasore, attenuated hyperoxia-mediated ROS production and p47 phox recruitment to CEMs. Using purified recombinant proteins, we observed that c-Abl tyrosine-phosphorylated dynamin 2, and this phosphorylation increased p47 phox /dynamin 2 association (change in the dissociation constant (K d ) from 85.8 to 6.9 nM). Furthermore, exposure of mice to hyperoxia increased ROS production, c-Abl activation, dynamin 2 association with p47 phox , and pulmonary leak, events that were attenuated in the caveolin-1 knock-out mouse confirming a role for CEMs in ROS generation. These results suggest that hyperoxia induces c-Abl-mediated dynamin 2 phosphorylation required for recruitment of p47 phox to CEMs and subsequent ROS production in lung endothelium.Vascular endothelial cell (EC) 2 barrier integrity is critical to normal vessel homeostasis with defects in the EC barrier contributing to inflammation, tumor angiogenesis, atherosclerosis, and acute lung injury (1). The generation of reactive oxygen species (ROS) in the vasculature plays a major role in EC activation and barrier function (2). Of the several potential sources of ROS in the vasculature, the endothelial NADPH oxidase family of proteins is a major contributor of ROS, and accumulation of ROS is associated with lung inflammation, ischemiareperfusion injury, sepsis, hyperoxia, and ventilator-associated lung injury (3). Activation of phagocytic NADPH oxidase requires the assembly of the cytosolic p47 phox , p67 phox , p40 phox , and Rac2 with membrane-associated cytochrome b 558 reductase, which consists of p22 phox and Nox2 (gp91 phox ). Vascular cells express similar subcomponents to phagocytic NADPH oxidase subunits, including Rac1, p47 phox , and Nox2 (2, 3). We have recently demonstrated that exposure of human pulmonary artery endothelial cells (HPAECs) to hyperoxia (95% O 2 ) increases the ROS production that is dependent on NADPH oxidase activation and independent of the mitochondrial electron transport or xanthine/xanthine oxidase systems (4).Regulation of NADPH oxidase activation in phagocytes requires serine phosphorylation of t...

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“…Earlier studies indicated that CD44 can function as a co-receptor to activate the signaling pathway through interacting with several growth factor receptors. [26][27][28] It is possible that CD44 functions as a co-receptor to potentiate the growth signaling in mast cells. As c-kit is the dominant receptor that regulates proliferation and differentiation of mast cells, c-kit is one of the possible partners of CD44 when it functions as a co-receptor.…”

Section: Mechanism Underlying Cd44-mediated Proliferationmentioning

confidence: 99%

Involvement of CD44 in mast cell proliferation during terminal differentiation

Takano

Nakazawa

Shirata

et al. 2009

Laboratory Investigation

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By using the recently established culture system that reproduces the terminal differentiation process of connective tissuetype mast cells, we found significant transcriptional induction of CD44. As CD44 is a primary receptor for hyaluronan (HA), which is one of the major extracellular matrix components, we investigated the role of CD44 in cutaneous mast cells. When co-cultured with fibroblasts, mouse bone marrow-derived cultured mast cells (BMMCs) were found to form clusters in an HA-dependent manner. As compared with BMMCs derived from the wild-type mice, those from the CD44 À/À mice exhibited impaired growth during the co-cultured period. Furthermore, in the peritoneal cavities and ear tissues, mature mast cells were fewer in number in the CD44 À/À mice than in the wild-type mice. We investigated roles of CD44 in mast cell proliferation by reconstituting BMMCs into the tissues of mast cell-deficient, Kit W /Kit W-v mice, and found that the number of metachromatic cells upon acidic toluidine blue staining in the tissues transplanted with CD44 À/À BMMCs was not significantly changed for 10 weeks, whereas that in the tissues transplanted with the CD44 þ / þ BMMCs was significantly increased. These results suggest that CD44 plays a crucial role in the regulation of the cutaneous mast cell number. As heterogeneity of tissue mast cells arise as a result of differences in the microenvironment that affects the process of the terminal differentiation, extensive investigation of the maturation process is required for precise understanding of the roles of tissue mast cells. Although several mast cell lines and IL-3-dependent bone marrow-derived cultured mast cells (BMMCs) have been used as models to investigate the process of mast cell activation and subsequent production of proinflammatory mediators, these models have limitations in analyzing functions specific to mature mast cells. Hence, recent studies have often employed the mast cell knock-in models using the mast cell-deficient mice, such as WBB6F1-) and C57BL/6-Kit), to investigate the roles of mature mast cells in vivo.1 By modifying the co-culturing method of BMMCs together with fibroblasts in the presence of stem cell factor (SCF), we have recently established a culture system for development of mature mast cells, which exhibit properties characteristic of connective tissue-type mast cells (CTMCs), such as degranulation induced by cationic secretagogues, Safranin-positive granules, and high levels of mast cell protease expression. 4 We then investigated the gene expression profile during the culture period and identified a cluster of candidate genes, which have potentials to modulate mast cell

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CD44 Regulates Hepatocyte Growth Factor-mediated Vascular Integrity

Cited by 108 publications

References 73 publications

HGF-induced invasion by prostate tumor cells requires anterograde lysosome trafficking and activity of Na+-H+ exchangers

HGF-induced invasion by prostate tumor cells requires anterograde lysosome trafficking and activity of Na+-H+ exchangers

Dynamin 2 and c-Abl Are Novel Regulators of Hyperoxia-mediated NADPH Oxidase Activation and Reactive Oxygen Species Production in Caveolin-enriched Microdomains of the Endothelium

Involvement of CD44 in mast cell proliferation during terminal differentiation

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