Altered interaction of Cis-dichlorodiammineplatinum(II)--modified alpha 2-macroglobulin (alpha 2M) with the low density lipoprotein receptor-related protein/alpha 2M receptor but not the alpha 2M signaling receptor.

Howard, Gayle C.; Misra, U. K.; DeCamp, Dianne L.; Pizzo, Salvatore V.

doi:10.1172/jci118533

Cited by 38 publications

(36 citation statements)

References 61 publications

(39 reference statements)

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“…1A). RBF binding site mutant K1370A induces signal transduction when it binds to macrophage ␣ 2 M* receptors, which belong to the class defined as ␣ 2 MSR (7,8). Addition of this mutant RBF also increased [ 3 H]lysoPC generation comparably to ␣ 2 M* or EGF (Fig.…”

Section: Western Blotting Of C-fos C-myc Creb and Nfb Proteins Inmentioning

confidence: 88%

“…In support of the identification of a distinct ␣ 2 M* receptor were several other observations. Two classes of binding sites were identified on macrophages, one of high affinity and low capacity (K d ϳ 50 pM and ϳ1600 sites/cell) and the other LRP, which demonstrated lower affinity and higher binding capacity (K d ϳ2-5 nM and ϳ70,000 sites/cell) (7)(8)(9)(10). Binding of other ligands to LRP, moreover, initiated signaling cascades that activated a pertussis toxin-sensitive G protein and were blocked by addition of RAP (4 -12).…”

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confidence: 99%

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Regulation of Cytosolic Phospholipase A2 Activity in Macrophages Stimulated with Receptor-recognized Forms of α2-Macroglobulin

Misra

Pizzo

2002

Journal of Biological Chemistry

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3 H]thymidine uptake and cell proliferation was completely abolished if activation of cPLA 2 was prevented. The response of macrophages to ␣ 2 M* requires transcription factors nuclear factor B, and cAMP-responsive element-binding protein as well as expression of the proto-oncogenes c-fos and c-myc. These studies indicate that the activation of cPLA 2 plays a crucial role in ␣ 2 M*-induced mitogenesis and cell proliferation.The plasma proteinase inhibitor ␣ 2 -macroglobulin (␣ 2 M*) 1 undergoes a major conformational change when it binds proteinases (1, 2). Each ␣ 2 M subunit also contains an internal thiol ester, which can be directly attacked by small nucleophiles resulting in a similar conformational change (1). In either event, receptor recognition sites are exposed in each of the subunits (1). These receptor-recognized forms of ␣ 2 M, termed ␣ 2 M*, bind to the low density lipoprotein receptorrelated protein (LRP) present on a variety of cells including macrophages (1-3). In 1993, we demonstrated that the binding of ␣ 2 M* to macrophages activated signaling cascades characterized by an inositol 1,4,5-trisphosphate (IP 3 )-dependent increase in [Ca 2ϩ ] i (4). Subsequent studies demonstrated that the binding to macrophages activates a pertussis toxin-insensitive phospholipase C, which hydrolyzes membrane phosphoinositides generating both IP 3 and diacylglycerol (5, 6). These studies also demonstrated that ␣ 2 M*-mediated signal transduction was not blocked by addition of receptor-associated protein (RAP). Because RAP blocks the binding of all known ligands to LRP, this observation suggested the presence of a second ␣ 2 M* receptor on macrophages, which was termed the ␣ 2 M* signaling receptor (␣ 2 MSR) (1, 5, 6). In support of the identification of a distinct ␣ 2 M* receptor were several other observations. Two classes of binding sites were identified on macrophages, one of high affinity and low capacity (K d ϳ 50 pM and ϳ1600 sites/cell) and the other LRP, which demonstrated lower affinity and higher binding capacity (K d ϳ2-5 nM and ϳ70,000 sites/cell) (7-10). Binding of other ligands to LRP, moreover, initiated signaling cascades that activated a pertussis toxin-sensitive G protein and were blocked by addition of RAP (4 -12). More recent observations, however, suggest that ␣ 2 M*-mediated signal transduction requires the presence of LRP on cells (13). Thus, Backsai et al. (13) have shown that ␣ 2 M* binding to LRP on neuronal cells mediates signaling via N-methyl-D-aspartate receptors. These authors suggest that an adapter protein causes LRP to associate with this receptor, allowing ␣ 2 M* to activate signal transduction. Furthermore, Herz and colleagues (14, 15) have identified a large number of adapter proteins that can associate with LRP, and Barnes et al. (16) have demonstrated that Tyr-phosphorylated LRP associates with the adapter protein SHC in SRC-transformed cells.Based on our observations with respect to activation of the p21 ras -dependent MAPK and PI 3-kinase signaling cascades and subseq...

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Section: Western Blotting Of C-fos C-myc Creb and Nfb Proteins Inmentioning

confidence: 88%

mentioning

confidence: 99%

Regulation of Cytosolic Phospholipase A2 Activity in Macrophages Stimulated with Receptor-recognized Forms of α2-Macroglobulin

Misra

Pizzo

2002

Journal of Biological Chemistry

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“…These cells still required proteinase inhibitors for cell spreading (data not shown). Other receptors not likely to be involved are the receptors for ␣ 2 M (34,38,39). These receptors recognize ␣ 2 M complexed with proteinase or ␣ 2 M treated with methylamine.…”

Section: Discussionmentioning

confidence: 99%

α1-Proteinase Inhibitor, α1-Antichymotrypsin, or α2-Macroglobulin Is Required for Vascular Smooth Muscle Cell Spreading in Three-dimensional Fibrin Gel

Ikari¹,

Fujikawa²,

Yee³

et al. 2000

Journal of Biological Chemistry

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It is assumed that vitronectin and other adhesion molecules induce cell spreading. We found that vascular smooth muscle cells require unidentified plasma components besides adhesion molecules to spread in fibrin gel, a likely provisional matrix at wound sites. By purification, the plasma components were found to be ␣ 1 -proteinase inhibitor, ␣ 1 -antichymotrypsin, and ␣ 2 -macroglobulin. The chemically inactivated ␣ 1 -proteinase inhibitor and ␣ 2 -macroglobulin lose the spreading activity, indicating that these proteins function as proteinase inhibitors but not as adhesion molecules. Not only antiintegrin (␣ v ␤ 3 and ␣ 5 ␤ 1 ) antibodies but also anti-fibronectin antibodies inhibit the cell spreading. The spreading occurs without the addition of fibronectin and integrins, suggesting that cells produce these molecules. In the absence of the proteinase inhibitors, Western blot analysis shows that the fibronectin is degraded in fibrin gel, while it is intact in the presence of the inhibitors. Thus, the proteinase inhibitors prevent adhesion molecules such as fibronectin from being degraded by a cell-derived proteinase(s) and thus play a role in cell spreading.Under physiological states, especially in wound healing and vascular injury, cell spreading has been observed in threedimensional matrices. In most of the studies, however, spreading has been conducted on artificial two-dimensional surfaces rather than in three-dimensional matrices. Cell spreading relates to the cells' ability to migrate, proliferate (1), and resist apoptosis (2). While fibrin is known as a blood coagulant protein, it has also been implicated in several forms of tissue response to injuries including angiogenesis (3), vascular disease (4, 5), wound healing (6), and metastasis of cancer (7,8). During in vitro experiments, we unexpectedly found that human smooth muscle cells do not spread in fibrin gel unless serum or plasma was added. Vitronectin, which is identified as the serum-spreading factor (9, 10), surprisingly did not promote the spreading. We then tested other molecules such as fibronectin, osteopontin, thrombospondin, platelet-derived growth factor, and plasminogen activator inhibitor type-1 (PAI-1) 1 as possible spreading factors. However, none of these factors were able to promote the cell spreading. We then attempted to purify the cell spreading factor(s) from bovine plasma and found that these are serine proteinase inhibitors. MATERIALS AND METHODSCell Spreading in Fibrin Gel-Cultured human vascular smooth muscle cells (HNB18E6E7) were originally derived from the aorta of a newborn infant (2 days old) autopsy (11,12). The cells were detached by brief exposure to 0.05% trypsin (Life Technologies, Inc.), 0.02% EDTA. The remaining trypsin was inactivated by an excess of soybean trypsin inhibitor (Sigma). After washing with 20 mM phosphate, pH 7.4, containing 0.15 M NaCl, the cells were resuspended at 62,500 cells/49 l in serum-free Dulbecco's modified Eagle's medium (Life Technologies, Inc.) containing 25 mM HEPES, pH 7.4. The cell ...

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“…␣ 2 M* was then labeled with Alexa Fluor (Molecular Probes). RAP was purified as previously described (22). Dr. J. Herz (University of Texas Southwestern Medical Center, Dallas, TX) kindly provided pGEX-RAP expression vectors.…”

Section: Protein Purification and Labelingmentioning

confidence: 99%

Cutting Edge: CD91-Independent Cross-Presentation of GRP94(gp96)-Associated Peptides

Berwin¹,

Hart

Pizzo

et al. 2002

The Journal of Immunology

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GRP94(gp96) elicits CD8+ T cell responses against its bound peptides, a process requiring access of its associated peptides into the MHC class I cross-presentation pathway of APCs. Entry into this pathway requires receptor-mediated endocytosis, and CD91 (low-density lipoprotein receptor-related protein) has been reported to be the receptor mediating GRP94 uptake into APC. However, a direct role for CD91 in chaperone-based peptide Ag re-presentation has not been demonstrated. We investigated the contribution of CD91 to GRP94 cell surface binding, internalization, and trafficking in APCs. Whereas a clear role for CD91 in α2-macroglobulin binding and uptake was readily obtained, the addition of excess CD91 ligand, activated α2-macroglobulin, or receptor-associated protein, an antagonist of all known CD91 ligands, did not affect GRP94 cell surface binding, receptor-mediated endocytosis, or peptide re-presentation. These data identify a CD91-independent, GRP94 internalization pathway that functions in peptide Ag re-presentation.

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Altered interaction of Cis-dichlorodiammineplatinum(II)--modified alpha 2-macroglobulin (alpha 2M) with the low density lipoprotein receptor-related protein/alpha 2M receptor but not the alpha 2M signaling receptor.

Abstract: Receptor-recognized forms of ␣ 2 -macroglobulin ( ␣ 2 M*) bind to two macrophage receptors: an endocytic receptor, the low density lipoprotein receptor-related protein/ ␣ 2 M receptor (LRP/ ␣ 2 MR), and a G protein-coupled receptor, the

Cited by 38 publications

References 61 publications

Regulation of Cytosolic Phospholipase A2 Activity in Macrophages Stimulated with Receptor-recognized Forms of α2-Macroglobulin

Regulation of Cytosolic Phospholipase A2 Activity in Macrophages Stimulated with Receptor-recognized Forms of α2-Macroglobulin

α1-Proteinase Inhibitor, α1-Antichymotrypsin, or α2-Macroglobulin Is Required for Vascular Smooth Muscle Cell Spreading in Three-dimensional Fibrin Gel

Cutting Edge: CD91-Independent Cross-Presentation of GRP94(gp96)-Associated Peptides

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