Role for Plastin in Host Defense Distinguishes Integrin Signaling from Cell Adhesion and Spreading

Chen, Hua; Mócsai, Attila; Zhang, Hong; Ding, Rongxian; Morisaki, J. Hiroshi; White, Michael J. V.; Rothfork, Jacob M.; Heiser, Patrick W.; Colucci‐Guyon, Emma; Lowell, Clifford A.; Gresham, Hattie D.; Allen, Paul M.; Brown, Eric J.

doi:10.1016/s1074-7613(03)00172-9

Cited by 96 publications

(127 citation statements)

References 56 publications

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“…However, the role of integrin signaling in the maturation of the sealing ring has not been studied well. Phosphorylation of L-plastin on serine residues is associated with the integrin activation (65). Localization of integrin ␣v␤3 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Sealing Ring Formation by L-plastin and Cortactin in Osteoclasts

Sadashivaiah

Chellaiah

2010

Journal of Biological Chemistry

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The aim of this study is to identify the exact mechanism(s) by which cytoskeletal structures are modulated during bone resorption. In this study, we have shown the possible role of different actin-binding and signaling proteins in the regulation of sealing ring formation. Our analyses have demonstrated a significant increase in cortactin and a corresponding decrease in L-plastin protein levels in osteoclasts subjected to bone resorption for 18 h in the presence of RANKL, M-CSF, and native bone particles. Time-dependent changes in the localization of L-plastin (in actin aggregates) and cortactin (in the sealing ring) suggest that these proteins may be involved in the initial and maturation phases of sealing ring formation, respectively. siRNA to cortactin inhibits this maturation process but not the formation of actin aggregates. Osteoclasts treated as above but with TNF-␣ demonstrated very similar effects as observed with RANKL. Osteoclasts treated with a neutralizing antibody to TNF-␣ displayed podosome-like structures in the entire subsurface and at the periphery of osteoclast. It is possible that TNF-␣ and RANKL-mediated signaling may play a role in the early phase of sealing ring configuration (i.e. either in the disassembly of podosomes or formation of actin aggregates). Furthermore, osteoclasts treated with alendronate or ␣v reduced the formation of the sealing ring but not actin aggregates. The present study demonstrates a novel mechanistic link between L-plastin and cortactin in sealing ring formation. These results suggest that actin aggregates formed by L-plastin independent of integrin signaling function as a core in assembling signaling molecules (integrin ␣v␤3, Src, cortactin, etc.) involved in the maturation process.Osteoclasts, the multinucleated and terminally differentiated giant cells, are involved in bone resorption. The adhesion of osteoclasts to the bone during bone resorption leads to the formation of the clear zone, an actin-rich ring-like adhesion zone circumscribing an area of bone resorption. Formation of a clear zone or sealing zone (also known as the sealing ring) has been considered to be a marker of osteoclast activation and is fundamental to the process of osteoclast bone resorption. Sealing ring formation is mediated by the dynamics of the actin cytoskeleton. Distinct pathways and signaling molecules have been shown to play roles in the organization of the sealing ring during bone resorption. Our previous observations in gelsolin null (Gsn Ϫ/Ϫ ) 2 osteoclasts demonstrated that deficiency of this protein blocks podosome assembly and motility. However, the cells still exhibit sealing ring and matrix resorption (1). Therefore, Gsn Ϫ/Ϫ osteoclasts are capable of resorbing bone, but the resorbed areas are small due to the absence of podosomes and the resulting hypomotile nature of osteoclasts (1). Observations in Gsn Ϫ/Ϫ osteoclasts also suggest that the organization of the sealing ring presumably reflect changes in the role of actinbinding proteins. Spatial configurations of actin fil...

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Section: Discussionmentioning

confidence: 99%

Regulation of Sealing Ring Formation by L-plastin and Cortactin in Osteoclasts

Sadashivaiah

Chellaiah

2010

Journal of Biological Chemistry

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“…Coronin-1A is localized to phagocytic vacuoles of neutrophils where the actin cytoskeleton mediates both phagocytic killing and binds p40 phox to activate NADPH oxidase driven production of superoxide. This latter process is also plastin mediated (96,100,101). Plastins further participate in cell invasion by the intracellular pathogens Salmonella and Shigella (100).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

Harrison

Dubois

John-Williams

et al. 2016

Molecular & Cellular Proteomics

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A thorough understanding of the molecular details of the interactions between bacteria and host are critical to ultimately prevent disease. Recent technological advances allow simultaneous analysis of host and bacterial protein and metabolic profiles from a single small tissue sample to provide insight into pathogenesis. We used the chinchilla model of human otitis media to determine, for the first time, the most expansive delineation of global changes in protein and metabolite profiles during an experimentally induced disease. After 48 h of infection with nontypeable Haemophilus influenzae, middle ear tissue lysates were analyzed by high-resolution quantitative two-dimensional liquid chromatography-tandem mass spectrometry. Dynamic changes in 105 chinchilla proteins and 66 metabolites define the early proteomic and metabolomic signature of otitis media. Our studies indicate that establishment of disease coincides with actin morphogenesis, suppression of inflammatory mediators, and bacterial aerobic respiration. We validated the observed increase in the actin-remodeling complex, Arp2/3, and experimentally showed a role for Arp2/3 in nontypeable Haemophilus influenzae invasion. Direct inhibition of actin branch morphology altered bacterial invasion into host epithelial cells, and is supportive of our efforts to use the information gathered to modify outcomes of disease. The twenty-eight nontypeable Haemophilus influenzae proteins identified participate in carbohydrate and amino acid metabolism, redox homeostasis, and include cell wall-associated metabolic proteins. Quantitative characterization of the molecular signatures of infection will redefine our understanding of host response driven developmental changes during pathogenesis. These data represent the first comprehensive study of host protein and metabolite profiles in vivo in response to infection and show the feasibility of extensive characterization of host protein profiles during disease. Identification of novel protein targets and metabolic biomarkers will advance development of therapeutic and diagnostic options for treatment of disease. Molecular & Cellular Proteomics 15: 10.1074/mcp.M115.052498, 1117-1138, 2016.Our current understanding of the global changes that occur during infection is primarily based upon transcriptional profiles of either the host or the bacteria. However, a significant component of disease progression is dependent upon posttranscriptional processes. Recent advances in the application of two-dimensional tandem mass spectrometry have dramatically increased sensitivity to allow simultaneous analyses of multiple molecules from very small biological samples. In this study, we report the comprehensive proteomic and metabolomic profiling of middle ear tissues using samples that are smaller than those typically obtained from a human biopsy. Proteomic and metabolomic analyses of samples as small as biopsies will revolutionize the elucidation of the mechanisms From the

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“…In line with this, in PMN derived from an L-plastin knock-out mouse, phosphorylation of paxillin and Syk upon adhesion to a polyRGDcoated surface were reduced. 44 Both proteins are known to be involved in actin cytoskeleton remodeling at adhesion sites.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of ectopically expressed L‐plastin enhances invasiveness of human melanoma cells

Klemke

Rafael

Wabnitz

et al. 2007

Intl Journal of Cancer

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The leukocyte specific actin-binding protein L-plastin is aberrantly expressed in several nonhematopoetic malignant tumors. However, little is known about the functional consequences of Lplastin expression. Here, we investigated the function of L-plastin in human malignant melanoma cells. Knock-down of endogenous L-plastin by siRNA treatment reduced migration of the melanoma cell line IF6. However, in melanoma patients, no correlation existed between L-plastin expression and tumor stages. This implied that additional factors such as phosphorylation of L-plastin may influence its function in tumor cells. To investigate this further, EGFP-tagged wild-type L-plastin (wt-LPL-EGFP) and a mutated, nonphosphorylatable L-plastin protein (5A7A-LPL-EGFP), were expressed in the L-plastin negative melanoma cell line MV3. Biochemical analysis revealed that wt-LPL-EGFP is phosphorylated in MV3 cells while 5A7A-LPL-EGFP is not. Although both wt-LPL-EGFP and 5A7A-LPL-EGFP were targeted to, and promote the formation of, vinculin-containing adhesion sites, static adhesion to either Matrigel or isolated extracellular matrix molecules was neither influenced by expression of wt-LPL-EGFP nor by expression of 5A7A-LPL-EGFP when compared with EGFP expressing control cells. In contrast, haptotactic, but not chemotactic, migration of melanoma cells towards either Matrigel or isolated extracellular matrix molecules was similarly enhanced, if either 5A7A-LPL-EGFP or wt-LPL-EGFP were expressed in MV3 cells. Interestingly, only cells expressing the phosphorylatable wt-LPL-EGFP protein showed enhanced invasion into Matrigel. In line with these findings the in vivo metastatic capacity of mouse B16 melanoma cells correlates with expression and phosphorylation of L-plastin. These data show that an increase in melanoma cell invasiveness requires not only expression but also phosphorylation of L-plastin. ' 2007 Wiley-Liss, Inc.Key words: migration; invasion; adhesion; L-plastin; melanoma Malignant melanoma is a very aggressive type of cancer that frequently metastasizes to distant organs. The capacity of tumor cells to form metastatic foci correlates with the ability to proteolytically degrade basement membrane barriers and to adhere to and migrate through extracellular matrix layers. 1,2 Two classes of molecules are mainly involved in these processes: the matrix metalloproteinases (MMPs) 3 and integrins. 4,5 Integrins are a large family of adhesion receptors involved in cell-cell and cellextracellular matrix interactions. They consist of heterodimers of 2 noncovalently associated a-and b-subunits. 6 The role of integrins in tumor cell metastasis has been intensively studied. 4,5,7 In human melanoma, especially b1-and b3-subunit containing integrins play important roles in metastasis, through an enhancement of adhesion, migration and invasion. 8,9 Moreover, the cell surface expression levels of many integrins can be directly correlated with the metastatic potential of melanoma cells. [10][11][12] Modulation of the actin cytoskeleton is critical f...

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Role for Plastin in Host Defense Distinguishes Integrin Signaling from Cell Adhesion and Spreading

Cited by 96 publications

References 56 publications

Regulation of Sealing Ring Formation by L-plastin and Cortactin in Osteoclasts

Regulation of Sealing Ring Formation by L-plastin and Cortactin in Osteoclasts

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

Phosphorylation of ectopically expressed L‐plastin enhances invasiveness of human melanoma cells

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