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Molecular and Cellular Biology, February 2001, p. 1185-1195, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1185-1195.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Identification of a Major Cyclic AMP-Dependent Protein Kinase A Phosphorylation Site within the Cytoplasmic Tail of the Low-Density Lipoprotein Receptor-Related Protein: Implication for Receptor-Mediated Endocytosis

Yonghe Li,1 Peter van Kerkhof,2 Maria Paz Marzolo,3 Ger J. Strous,2 and Guojun Bu1,*

Departments of Pediatrics and of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 631101; Department of Cell Biology, Utrecht University, Utrecht, The Netherlands2; and Department of Biology, University of Chile, Santiago, Chile3

Received 28 September 2000/Accepted 15 November 2000

The low-density lipoprotein (LDL) receptor-related protein (LRP) is a multiligand endocytic receptor that belongs to the LDL receptor family. Recently, studies have revealed new roles of LDL receptor family members as transducers of extracellular signals. Our previous studies have demonstrated LRP phosphorylation within its cytoplasmic tail, but the nature of LRP phosphorylation and its potential function was unknown. In the present study using both in vivo and in vitro analysis, we found that LRP phosphorylation is mediated by the cAMP-dependent protein kinase A (PKA). Using site-directed mutagenesis and LRP minireceptor constructs, we further identified the predominant LRP phosphorylation site at serine 76 of its cytoplasmic tail. Finally, we demonstrated that mutations of serine 76, which abolish LRP phosphorylation by PKA, result in a decrease in the initial endocytosis rate of LRP and a lower efficiency in delivery of ligand for degradation. Thus, the role of PKA phosphorylation of LRP in receptor-mediated endocytosis may provide a mechanism by which the endocytic function of LRP can be regulated by external signals.

* Corresponding author. Mailing address: Department of Pediatrics, Washington University School of Medicine, CB 8208, 660 South Euclid Ave., St. Louis, MO 63110. Phone: (314) 286-2860. Fax: (314) 286-2894. E-mail: bu{at}kids.wustl.edu.

Molecular and Cellular Biology, February 2001, p. 1185-1195, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1185-1195.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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