Publication Detail

The publication detail shows the title, authors (with indicators showing other profiled authors), information on the publishing organization, abstract and a link to the article in PubMed. This abstract is what is used to create the fingerprint of the publication. If any grants are referenced by the publication, they will be listed here as well.

Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase Calpha regulates endocytosis and association with adaptor molecules.

Sripriya Ranganathan; Chun-Xiang Liu; Mary M Migliorini; Christine A F Von Arnim; Ithan D Peltan; Irina Mikhailenko; Bradley T Hyman; Dudley K Strickland (Profiled Authors: Irina Mikhailenko; Dudley K Strickland)

Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
The Journal of biological chemistry 2004;279(39):40536-44.

The low density lipoprotein receptor-related protein (LRP) is a large receptor that participates in endocytosis, signaling pathways, and phagocytosis of necrotic cells. Mechanisms that direct LRP to function in these distinct pathways likely involve its association with distinct cytoplasmic adaptor proteins. We tested the hypothesis that the association of various adaptor proteins with the LRP cytoplasmic domain is modulated by its phosphorylation state. Phosphoamino acid analysis of metabolically labeled LRP revealed that this receptor is phosphorylated at serine, threonine, and tyrosine residues within its cytoplasmic domain, whereas inhibitor studies identified protein kinase Calpha (PKCalpha) as a kinase capable of phosphorylating LRP. Mutational analysis identified critical threonine and serine residues within the LRP cytoplasmic domain that are necessary for phosphorylation mediated by PKCalpha. Mutating these threonine and serine residues to alanines generated a receptor that was not phosphorylated and that was internalized more rapidly than wild-type LRP, revealing that phosphorylation reduces the association of LRP with adaptor molecules of the endocytic machinery. In contrast, serine and threonine phosphorylation was necessary for the interaction of LRP with Shc, an adaptor protein that participates in signaling events. Furthermore, serine and threonine phosphorylation increased the interaction of LRP with other adaptor proteins such as Dab-1 and CED-6/GULP. These results indicate that phosphorylation of LRP by PKCalpha modulates the endocytic and signaling function of LRP by modifying its association with adaptor proteins.

2 Originating Grant

• 1.

  STRICKLAND, DUDLEY K.

  Information Signaling Pathways in the Vasculature

  1 May 1997 - 31 March 2012

  NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

• 2.

  STRICKLAND, DUDLEY K.

  Regulation of Surface Receptors by LRP

  30 September 1993 - 30 June 2012

  NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

Scientific Context

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