Nerve Growth Factor Induces Rapid Increases in Functional Cell Surface Low Density Lipoprotein Receptor-related Protein

Speed and selectivity of hepatocyte invasion by malaria sporozoites have suggested a receptor-mediated mechanism and the specific interaction of the circumsporozoite (CS) protein with liver-specific heparan sulfate proteoglycans (HSPGs) has been implicated in the targeting to the liver. Here we show that the CS protein interacts not only with cell surface heparan sulfate, but also with the low density lipoprotein receptor-related protein (LRP). Binding of 125I-CS protein to purified LRP occurs with a Kd of 4.9 nM and can be inhibited by the receptor-associated protein (RAP). Blockage of LRP by RAP or anti-LRP antibodies on heparan sulfate-deficient CHO cells results in more than 90% inhibition of binding and endocytosis of recombinant CS protein. Conversely, blockage or enzymatic removal of the cell surface heparan sulfate from LRP-deficient embryonic mouse fibroblasts yields the same degree of inhibition. Heparinase-pretreatment of LRP-deficient fibroblasts or blockage of LRP on heparan sulfate-deficient CHO cells by RAP, lactoferrin, or anti-LRP antibodies reduces Plasmodium berghei invasion by 60-70%. Parasite development in heparinase-pretreated HepG2 cells is inhibited by 65% when RAP is present during sporozoite invasion. These findings suggest that malaria sporozoites utilize the interaction of the CS protein with HSPGs and LRP as the major mechanism for host cell invasion.

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Epidermal Growth Factor and Platelet-derived Growth Factor-BB Induce a Stable Increase in the Activity of Low Density Lipoprotein Receptor-related Protein in Vascular Smooth Muscle Cells by Altering Receptor Distribution and Recycling

Journal of Biological Chemistry ◽

10.1074/jbc.271.40.24894 ◽

1996 ◽

Vol 271 (40) ◽

pp. 24894-24900 ◽

Cited By ~ 34

Author(s):

Alissa M. Weaver ◽

Megan McCabe ◽

Ian Kim ◽

Margaretta M. Allietta ◽

Steven L. Gonias

Keyword(s):

Growth Factor ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Platelet Derived Growth Factor ◽

Low Density ◽

Lipoprotein Receptor ◽

Related Protein ◽

Density Lipoprotein Receptor ◽

Epidermal Growth ◽

Lipoprotein Receptor Related Protein

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Low density lipoprotein receptor–related protein is a calreticulin coreceptor that signals focal adhesion disassembly

The Journal of Cell Biology ◽

10.1083/jcb.200302069 ◽

2003 ◽

Vol 161 (6) ◽

pp. 1179-1189 ◽

Cited By ~ 104

Author(s):

Anthony Wayne Orr ◽

Claudio E. Pedraza ◽

Manuel Antonio Pallero ◽

Carrie A. Elzie ◽

Silvia Goicoechea ◽

...

Keyword(s):

Cell Surface ◽

Focal Adhesion ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density ◽

Lipoprotein Receptor ◽

Related Protein ◽

Low Density Lipoprotein Receptor ◽

Density Lipoprotein Receptor ◽

Lipoprotein Receptor Related Protein

Thrombospondin (TSP) signals focal adhesion disassembly (the intermediate adhesive state) through interactions with cell surface calreticulin (CRT). TSP or a peptide (hep I) of the active site induces focal adhesion disassembly through binding to CRT, which activates phosphoinositide 3-kinase (PI3K) and extracellular signal–related kinase (ERK) through Gαi2 proteins. Because CRT is not a transmembrane protein, it is likely that CRT signals as part of a coreceptor complex. We now show that low density lipoprotein receptor–related protein (LRP) mediates focal adhesion disassembly initiated by TSP binding to CRT. LRP antagonists (antibodies, receptor-associated protein) block hep I/TSP-induced focal adhesion disassembly. LRP is necessary for TSP/hep I signaling because TSP/hep I is unable to stimulate focal adhesion disassembly or ERK or PI3K signaling in fibroblasts deficient in LRP. LRP is important in TSP–CRT signaling, as shown by the ability of hep I to stimulate association of Gαi2 with LRP. The isolated proteins LRP and CRT interact, and LRP and CRT are associated with hep I in molecular complexes extracted from cells. These data establish a mechanism of cell surface CRT signaling through its coreceptor, LRP, and suggest a novel function for LRP in regulating cell adhesion.

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