The role of protein tyrosine phosphorylation in integrin-mediated gene induction in monocytes.

Lin, Tsung H.; Yurochko, Andrew D.; Kornberg, Lori; Morris, J. Steven; Walker, J.J.; Haskill, Stephen; Juliano, Rudolph L.

doi:10.1083/jcb.126.6.1585

Cited by 113 publications

(70 citation statements)

References 56 publications

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“…kinase activity, trigger signal transduction events (22). For example, the adherence of human monocytes to ECM or ligation of their ␤ 1 integrins with antibodies triggers an increase in tyrosine phosphorylation of several proteins and the expression of immediate-early genes (23,24). As reported here, incubation of RAW264.7 macrophages with ␣1:SRARKQAASIKVAVSADR stimulated tyrosine phosphorylation and the expression of uPA and MMP-9.…”

Section: Discussionmentioning

confidence: 59%

Selective Activation of MAPKerk1/2 by Laminin-1 Peptide α1:Ser2091–Arg2108 Regulates Macrophage Degradative Phenotype

Khan

Falcone

2000

Journal of Biological Chemistry

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Components of the extracellular matrix contain cryptic domains, which are exposed by proteolysis and elicit biological responses distinct from intact molecules. The disparate cellular response to extracellular matrix fragments and parent intact molecules suggests differential recognition and signaling pathways. In experiments reported here, we demonstrate that urokinase and matrix metalloproteinase-9 expression by RAW264.7 macrophages is stimulated by a synthetic laminin peptide derived from the ␣1-chain (SRARKQAASIKVAVSADR), whereas intact laminin-1 has no effect on proteinase expression by macrophages. Incubation of macrophages with ␣1:SRARKQAASIKVAVSADR stimulates tyrosine phosphorylation of several proteins including mitogenactivated protein kinase (MAPK) erk1/2 . In contrast, neither intact laminin-1 nor the ␤1-chain peptide CDPGY-IGSR stimulated protein tyrosine phosphorylation in these cells. Inhibition of tyrosine kinases or protein kinase C blocked ␣1-chain peptide-induced phosphorylation of MAPK erk1/2 and the up-regulation of steady state levels of urokinase mRNA and matrix metalloproteinase-9 activity. A MAPK kinase inhibitor blocked ␣1-chain-induced phosphorylation of MAPK erk1/2 and the induction of proteinase expression. Intact laminin-1, which was unable to induce macrophage proteinase expression, failed to stimulate the phosphorylation of MAPK erk1/2 . These data demonstrate that incubation of macrophages with ␣1:SRARKQAASIKVAVSADR, but not intact laminin-1, triggers protein kinase C-dependent activation of MAPK erk1/2 , leading to the up-regulation of proteinase expression.Evidence is emerging that components of extracellular matrix (ECM) 1 contain cryptic domains, which are exposed by proteolysis and elicit biological responses distinct from intact molecules (1, 2). For example, it was recently reported that matrix metalloproteinase-2 (MMP-2) degrades laminin-5, leading to the exposure of a hidden site that stimulates cell motility (3). Fragments of elastin and fibronectin may play an important role in the recruitment of neutrophils and monocytes following tissue injury (4 -6). A fragment of fibronectin triggers AP-1, whereas intact fibronectin does not (1). Finally, it has been reported that a fragment of collagen XIII is antiangiogenic (7).In previous studies, we reported that urokinase (uPA) and MMP-9 expression by macrophages and macrophage cell lines were up-regulated when cultured on extracellular matrix purified from Engelbreth Holm Swarm (EHS) sarcomas (8). In order to identify the ECM components that were responsible for the increase in the proteinase expression of macrophages, cells were incubated with human collagen IV, fibronectin, and tenascin. Each of these purified ECM components stimulated cellular MMP-9 expression. In contrast, both uPA and MMP-9 expressions were stimulated by laminin isolated from human placental following mild pepsin digestion. The effect of placental laminin on uPA expression was mirrored by SIKVAV, a synthetic laminin peptide derived from the tail region o...

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Section: Discussionmentioning

confidence: 59%

Selective Activation of MAPKerk1/2 by Laminin-1 Peptide α1:Ser2091–Arg2108 Regulates Macrophage Degradative Phenotype

Khan

Falcone

2000

Journal of Biological Chemistry

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“…In addition to providing scaffolding for cells to attach, engagement of the ECM profoundly regulates monocyte/macrophage gene expression (49,50,58). Cellular engagement of ECM components, which is largely integrin-mediated, triggers tyrosine phosphorylation of several proteins including MAPK erk1/2 (42,49,51,52,59). The MAPK superfamily is a major signaling pathway by which extracellular signals regulate gene expression (53,60).…”

Section: Discussionmentioning

confidence: 99%

Extracellular Matrix-induced Cyclooxygenase-2 Regulates Macrophage Proteinase Expression

Khan

Howe

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2004

Journal of Biological Chemistry

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Chronic inflammatory diseases are characterized by the persistent presence of macrophages and other mononuclear cells, tissue destruction, cell proliferation, and the deposition of extracellular matrix (ECM). The tissue degradation is mediated, in part, by enhanced proteinase expression by macrophages. It has been demonstrated recently that macrophage proteinase expression can be stimulated or inhibited by purified ECM components. However, in an intact ECM the biologically active domains of matrix components may be masked either by tertiary conformation or by complex association with other matrix molecules. In an effort to determine whether a complex ECM produced by vascular smooth muscle cells (SMC) regulates macrophage degradative phenotype, we prepared insoluble SMC matrices and examined their ability to regulate proteinase expression by RAW264.7 and thioglycollate-elicited peritoneal macrophages. Here we demonstrate that macrophage engagement of SMC-ECM triggers PKC-dependent activation of MAPK erk1/2 leading to increased expression of cyclooxygenase (COX)-2 and prostaglandin (PG) E 2 synthesis. The addition of PGE 2 to macrophage cultures stimulates their expression of both urokinase-type plasminogen activator and MMP-9, and the selective COX-2 inhibitor NS-398 blocks ECMinduced proteinase expression. Moreover, ECM-induced PGE 2 and MMP-9 expression by elicited COX-2 ؊/؊ macrophages is markedly reduced when compared with the response of either COX-2 ؉/؊ or COX-2 ؉/؉ macrophages. These data clearly demonstrate that SMC-ECM exerts a regulatory role on the degradative phenotype of macrophages via enhanced urokinase-type plasminogen activator and MMP-9 expression, and identify COX-2 as a targetable component of the signaling pathway leading to increased proteinase expression.The structural integrity of tissue is compromised in a variety of inflammatory settings by macrophage expression of serine and matrix metalloproteinases (MMPs). 1 Principal among the serine proteinases is urokinase-type plasminogen activator (uPA) (1). Cleavage of plasminogen by uPA generates plasmin, which binds to and degrades fibrin and components of the ECM (2-4). Several studies have demonstrated that uPA-dependent plasminogen activation regulates macrophage migration (5-7), degradation of extracellular matrices (7-9) and fibrin (10, 11), and the release of matrix-bound growth factors (12-14). Moreover, the important role of plasminogen activation in macrophage migration and clearance of fibrin and necrotic tissue following injury has been confirmed by utilizing mice deficient in components of the uPA-plasminogen system (15)(16)(17)(18)(19)(20).In addition to the uPA/plasminogen system, macrophages express MMPs, which are associated with tissue remodeling via their ability to degrade ECM components (21,22). Macrophages, depending on their origin and state of activation, express several members of the MMP family including MMP-9 (23, 24). As observed for the uPA/plasminogen system, several studies have suggested a role for MMP-9 in cell ...

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“…57 Furthermore, integrin-initiated signals stimulate the tyrosine phosphorylation of a number of cellular proteins. 57,58 The inhibition of tyrosine phosphorylation blocks adhesion-induced gene expression 59 and localization of integrins to focal contacts. 60 These outside-in signaling events regulate not only gene induction, cell growth and differentiation but also cell migration and synthesis of MMPs.…”

Section: Discussionmentioning

confidence: 99%

Role of ?1 integrins in adhesion and invasion of hepatocellular carcinoma cells

1999

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To investigate the role of integrins in hepatocellular carcinoma (HCC) invasion, we analyzed the relationship between the expression and activity of ␤1 integrins and the invasive ability of multiple HCC cell lines. Human HCC cell lines, PLC/PRF/5, Hep3B, HepG2, HLE, HuH7, and C3A cells, had high expression of ␤1 and ␣6 subunits, and various levels of ␣1, ␣2, ␣3, and ␣5 expression as determined by cell surface flow cytometry. Activity of ␤1 integrins was evaluated by cell adhesion to collagen, fibronectin, and laminin in the presence or absence of the stimulatory anti-␤1 monoclonal antibody ( Tumor invasion and metastasis are complex processes requiring the ability of tumor cells to interact with endothelial cells and extracellular matrix. The major cell surface receptors that mediate these interactions are integrins. They are heterodimeric transmembrane receptors consisting of ␣ and ␤ subunits, which produce more than 20 different heterodimers and bind specific ligands. 1,2 Each subunit is a glycoprotein with a large extracellular domain and a relatively small cytoplasmic domain. It has been shown that integrins can transduce signals and play principal roles in biological features of tumors, especially in growth, differentiation, and invasive and metastatic events of malignant cells. 2,3 Changes in expression of integrins have been linked to both tumor suppression and tumor progression in different human malignancies. 4,5 Several studies have described altered expression of ␤1 integrins in hepatocellular carcinoma (HCC). Reduced expression of ␣2, ␣3, and ␣5 subunits 6,7 and overexpression of ␣6 subunits of ␤1 integrins 8 have been shown in HCC with aggressive phenotypes. Nonpolarized aberrant distribution of ␤1 subunit has been shown to correlate with tumor growth rate, grade, and size in HCC. 9 These observations suggest important roles of ␤1 integrins in growth and invasiveness of HCC. Recently, several studies have indicated the modulation of expression and function of ␤1 integrins on HCC cells during metastatic events. Following the adhesion to vascular endothelial cells, HCC cells receive stimulation from cytokines produced by the endothelial cells. The resultant increase of ␣2␤1 integrin expression on HCC cells may facilitate migration of these cells to extravascular tissues. 10 On the contrary, the cell adhesion regulator, the gene of which is located on 16q, suppresses the process of integrin-mediated cell adhesion and has an inhibitory effect on the progression of HCC. 11

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The role of protein tyrosine phosphorylation in integrin-mediated gene induction in monocytes.

Cited by 113 publications

References 56 publications

Selective Activation of MAPKerk1/2 by Laminin-1 Peptide α1:Ser2091–Arg2108 Regulates Macrophage Degradative Phenotype

Selective Activation of MAPKerk1/2 by Laminin-1 Peptide α1:Ser2091–Arg2108 Regulates Macrophage Degradative Phenotype

Extracellular Matrix-induced Cyclooxygenase-2 Regulates Macrophage Proteinase Expression

Role of ?1 integrins in adhesion and invasion of hepatocellular carcinoma cells

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