Brief reviewPhosphorylation of LRP1: Regulation of Transport and Signal Transduction
Section snippets
A Giant Receptor that Mediates Internalization of a Variety of Proteins and Lipoproteins
The characterization of defects in lipoprotein metabolism in animals or patients with defective LDLRs led to the conclusion that there are additional LDLR-like proteins (Kita et al. 1982). The first LDLR-related protein to be identified was LRP1. LRP1 is a very large protein that is composed of 4525 amino acids (Herz et al. 1988). The 15-kb mRNA is translated into a polypeptide precursor with a single transmembrane domain. This precursor protein is cleaved in the Golgi apparatus by a furin-like
Phosphorylation of LRP1 by Protein Kinase A
Phosphorylation has been found to be important in the targeting of cell-surface proteins for internalization or degradation in a variety of systems Ferguson 2001, Waterman and Yarden 2001. This prompted Holtzman and coworkers to test whether LRP1 is phosphorylated following stimulation of cells with growth factors. Because LRP1 is highly expressed in the nervous system, they analyzed LRP1 phosphorylation in two neuronal cell lines and found that it becomes phosphorylated in response to nerve
Tyrosine Phosphorylation of LRP1
Our interest in substrate recognition by the Src protein–tyrosine kinase led to the discovery that LRP1 can become phosphorylated on tyrosine residues and that tyrosine-phosphorylated LRP1 associates with Shc (Barnes et al. 2001). Src was originally identified as the transforming protein of a retrovirus that causes tumors in chickens. It is the founding member of a family of related cytoplasmic protein–tyrosine kinases that includes eight members (Abram and Courtneidge 2000). Members of this
Phosphorylation of LRP1: A Story of Regulation and Signal Transduction
It is now well established that LRP1 is phosphorylated under a variety of conditions. This can be interpreted in two different ways. One interpretation is that LRP1 itself acts as a signal transducing receptor and that phosphorylation is the first step in the activation of signaling proteins and the initiation of one or more signal transduction cascades. Alternatively, LRP1 could be the end point of a signal transduction cascade that is aimed at modifying the activity of LRP1. These two
A Family of Signal Transducing Receptors
The cytoplasmic domain of the LDLR contains only 50 amino acids and a single NPXY motif. This indicates that 50 residues contain all the structural information needed to connect the LDLR to the cellular machinery that mediates internalization of the receptor and circulation back to the plasma membrane. Other members of this family contain cytoplasmic domains of 60 to 220 residues with one to three NPXY motifs. These cytoplasmic domains are larger than necessary for the execution of receptor
Signal Transduction by LRP1: A Question of Dimerization
Evidence that LRP1 is phosphorylated on tyrosine residues combined with the observation that LRP1 can associate with signaling proteins such as Shc, Disabled, and FE65 suggests that it is indeed a signaling receptor. This idea is supported by studies that show that other members of the LDLR family are also engaged in signal transduction. There are at least two possible models for signaling through LRP1. In the first model, ligand binding results in LRP1 homodimerization (Figure 4). Dimerization
Future Directions
Binding of α2M to LRP1 was shown to stimulate Ca2+ mobilization. The pathways that lead from LRP1 to NMDA-mediated Ca2+ release remain to be explored. There are three serine residues present in the cytoplasmic domain of LRP1. Two of them have been identified as PKA phosphorylation sites. The next important question is to find out which protein–protein interactions are affected by phosphorylation of Ser 73 and Ser 76. The cytoplasmic domain of LRP1 also contains four tyrosine residues. It
Acknowledgements
The author would like to thank Helen Barnes, Mark Barsoum, Jeremy Copp, and Sandy Wiley for helpful discussions and comments on the manuscript. This work was supported by a grant from the National Institute of Health (1R29 CA78629).
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