The 39-kDa Receptor-associated Protein Modulates Lipoprotein Catabolism by Binding to LDL Receptors

Medh, Jheem D.; Fry, Glenna L.; Bowen, Susan L.; Pladet, M W; Strickland, Dudley K.; Chappell, David

doi:10.1074/jbc.270.2.536

Cited by 113 publications

(94 citation statements)

References 46 publications

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“…RAP is an intracellular chaperone that binds tightly to the LRP1 α-chain, with the pitfall that other members of the LDL receptor family are also detected (38,39). In uninjured rat sciatic nerve, a single band with an apparent mass equivalent to that of the LRP1 α-chain was observed ( Figure 1C).…”

Section: Resultsmentioning

confidence: 99%

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A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

Gaultier

Arandjelovic

et al. 2008

J. Clin. Invest.

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Injury to the peripheral nervous system (PNS) initiates a response controlled by multiple extracellular mediators, many of which contribute to the development of neuropathic pain. Schwann cells in an injured nerve demonstrate increased expression of LDL receptor-related protein-1 (LRP1), an endocytic receptor for diverse ligands and a cell survival factor. Here we report that a fragment of LRP1, in which a soluble or shed form of LRP1 with an intact α-chain (sLRP-α), was shed by Schwann cells in vitro and in the PNS after injury. Injection of purified sLRP-α into mouse sciatic nerves prior to chronic constriction injury (CCI) inhibited p38 MAPK activation (P-p38) and decreased expression of TNF-α and IL-1β locally. sLRP-α also inhibited CCI-induced spontaneous neuropathic pain and decreased inflammatory cytokine expression in the spinal dorsal horn, where neuropathic pain processing occurs. In cultures of Schwann cells, astrocytes, and microglia, sLRP-α inhibited TNF-α-induced activation of p38 MAPK and ERK/MAPK. The activity of sLRP-α did not involve TNF-α binding, but rather glial cell preconditioning, so that the subsequent response to TNF-α was inhibited. Our results show that sLRP-α is biologically active and may attenuate neuropathic pain. In the PNS, the function of LRP1 may reflect the integrated activities of the membrane-anchored and shed forms of LRP1.

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Section: Resultsmentioning

confidence: 99%

“…Most LRP1 ligands bind to clusters of complement-like repeats in the α-chain, which may be fully blocked by GST-RAP (1,11,38,39). Two protocols were executed to test whether GST-RAP inhibits the activity of sLRP-α in vivo in the injured nerve.…”

Section: Figurementioning

confidence: 99%

A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

Gaultier

Arandjelovic

et al. 2008

J. Clin. Invest.

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“…The receptors have high affinity for their ligands and broad specificity. They recognize not only lipoproteins but also a variety of nonlipoprotein ligands, including urokinase and tissue plasminogen activator with their inhibitors and participate in different physiological processes (26,(37)(38)(39)(40)(41)(42)(43)(44)(45). Ten members of this family are known to date: the LDL receptor itself, ␣ 2 -macroglobulin receptor/low density lipoprotein receptor-related protein (␣ 2 MR/LRP), very low density lipoprotein receptor, Heymann nephritis antigen/ megalin/gp330, chicken vitellogenin receptor, Drosophila Yolkless, chicken LR8B, placental calcium sensor protein (29), the newly discovered apolipoprotein E receptor 2 (apoER2) (30), and LR11 (31).…”

Section: Discussionmentioning

confidence: 99%

Collagenase-3 Binds to a Specific Receptor and Requires the Low Density Lipoprotein Receptor-related Protein for Internalization

Barmina

Walling

Fiacco

et al. 1999

Journal of Biological Chemistry

111

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We have previously identified a specific receptor for collagenase-3 that mediates the binding, internalization, and degradation of this ligand in UMR 106-01 rat osteoblastic osteosarcoma cells. In the present study, we show that collagenase-3 binding is calcium-dependent and occurs in a variety of cell types, including osteoblastic and fibroblastic cells. We also present evidence supporting a two-step mechanism of collagenase-3 binding and internalization involving both a specific collagenase-3 receptor and the low density lipoprotein receptorrelated protein. Ligand blot analysis shows that 125 Icollagenase-3 binds specifically to two proteins (ϳ170 kDa and ϳ600 kDa) present in UMR 106-01 cells. Western blotting identified the 600-kDa protein as the low density lipoprotein receptor-related protein. Our data suggest that the 170-kDa protein is a specific collagenase-3 receptor. Low density lipoprotein receptor-related protein-null mouse embryo fibroblasts bind but fail to internalize collagenase-3, whereas UMR 106-01 and wildtype mouse embryo fibroblasts bind and internalize collagenase-3. Internalization, but not binding, is inhibited by the 39-kDa receptor-associated protein. We conclude that the internalization of collagenase-3 requires the participation of the low density lipoprotein receptor-related protein and propose a model in which the cell surface interaction of this ligand requires a sequential contribution from two receptors, with the collagenase-3 receptor acting as a high affinity primary binding site and the low density lipoprotein receptor-related protein mediating internalization. Collagenase-3 (MMP-13)1 is a member of the matrix metalloproteinase family of enzymes, which participates in extracellular matrix remodeling (1). Members of this family have a number of structural and functional features in common. In addition to sharing a similar domain structure, all are synthesized in inactive form, function at neutral pH, and require intrinsic zinc and calcium ions for their activity. Collagenase-3 is a highly regulated enzyme that cleaves native fibrillar collagens of types I, II, and III. The 57-kDa proenzyme is converted to its active 52-kDa form by the plasmin activation cascade, as well as by cathepsin B, stromelysin, and plasma kallikrein (2, 3). Collagenase-3 activity is inhibited by a family of tissue inhibitors of metalloproteinases (4, 5). A range of hormones and agents can also regulate expression of collagenase-3 (6). Parathyroid hormone is one of the hormones participating in this process. Osteoblastic cells respond to parathyroid hormone by increasing collagenase-3 synthesis (6 -8), plasminogen activator activity (9), and tissue inhibitors of metalloproteinases expression (8). In addition, experiments with UMR 106-01 rat osteosarcoma cells showed that over 80% of exogenous rat collagenase-3 was removed from the medium after 8 h of incubation (10). This rapid removal of rat collagenase-3 from the medium suggested the existence of a specific receptor that represents another level of regu...

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“…As shown in Fig. 6A, neither the inhibitory antibodies against CRT or LRP1 (46) nor LRP1 receptorassociated protein (RAP), which inhibits CRT-LRP1 binding (43,47,48), showed inhibition on LPS/cytokine-activated PEM phagocytosis toward RBCs and splenocytes. However, these same reagents significantly inhibited phagocytosis toward apoptotic cells (Fig.…”

Section: What Is the Phagocytic Receptor On Macrophages For Uptakingmentioning

confidence: 92%

Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells

Bian

Shi

Guo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

121

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Rapid clearance of adoptively transferred Cd47-null (Cd47−/−) cells in congeneic WT mice suggests a critical self-recognition mechanism, in which CD47 is the ubiquitous marker of self, and its interaction with macrophage signal regulatory protein α (SIRPα) triggers inhibitory signaling through SIRPα cytoplasmic immunoreceptor tyrosine-based inhibition motifs and tyrosine phosphatase SHP-1/2. However, instead of displaying self-destruction phenotypes, Cd47−/− mice manifest no, or only mild, macrophage phagocytosis toward self-cells except under the nonobese diabetic background. Studying our recently established Sirpα-KO (Sirpα−/−) mice, as well as Cd47−/− mice, we reveal additional activation and inhibitory mechanisms besides the CD47-SIRPα axis dominantly controlling macrophage behavior. Sirpα−/− mice and Cd47−/− mice, although being normally healthy, develop severe anemia and splenomegaly under chronic colitis, peritonitis, cytokine treatments, and CFA-/LPS-induced inflammation, owing to splenic macrophages phagocytizing self-red blood cells. Ex vivo phagocytosis assays confirmed general inactivity of macrophages from Sirpα−/− or Cd47−/− mice toward healthy self-cells, whereas they aggressively attack toward bacteria, zymosan, apoptotic, and immune complex-bound cells; however, treating these macrophages with IL-17, LPS, IL-6, IL-1β, and TNFα, but not IFNγ, dramatically initiates potent phagocytosis toward self-cells, for which only the Cd47-Sirpα interaction restrains. Even for macrophages from WT mice, phagocytosis toward Cd47−/− cells does not occur without phagocytic activation. Mechanistic studies suggest a PKC-Syk–mediated signaling pathway, to which IL-10 conversely inhibits, is required for activating macrophage self-targeting, followed by phagocytosis independent of calreticulin. Moreover, we identified spleen red pulp to be one specific tissue that provides stimuli constantly activating macrophage phagocytosis albeit lacking in Cd47−/− or Sirpα−/− mice.

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The 39-kDa Receptor-associated Protein Modulates Lipoprotein Catabolism by Binding to LDL Receptors

Cited by 113 publications

References 46 publications

A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

Collagenase-3 Binds to a Specific Receptor and Requires the Low Density Lipoprotein Receptor-related Protein for Internalization

Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells

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