The members of the low density lipoprotein (LDL) receptor gene family bind a broad spectrum of extracellular ligands. Traditionally, they had been regarded as mere cargo receptors that promote the endocytosis and lysosomal delivery of these ligands. However, recent genetic experiments in mice have revealed critical functions for two LDL receptor family members, the very low density lipoprotein receptor and the apoE receptor-2, in the transmission of extracellular signals and the activation of intracellular tyrosine kinases. This process regulates neuronal migration and is crucial for brain development. Signaling through these receptors requires the interaction of their cytoplasmic tails with the intracellular adaptor protein Disabled-1 (DAB1). Here, we identify an extended set of cytoplasmic proteins that might also participate in signal transmission by the LDL receptor gene family. Most of these novel proteins are adaptor or scaffold proteins that contain PID or PDZ domains and function in the regulation of mitogen-activated protein kinases, cell adhesion, vesicle trafficking, or neurotransmission. We show that binding of DAB1 interferes with receptor internalization suggesting a mechanism by which signaling through this class of receptors might be regulated. Taken together, these findings imply much broader physiological functions for the LDL receptor family than had previously been appreciated. They form the basis for the elucidation of the molecular pathways by which cells respond to the diversity of ligands that bind to these multifunctional receptors on the cell surface.
"Our finding that interaction between GIPC and LPA1 leads to downregulation of Akt signaling has important pathophysiological implications, given 1) that LPA1 has been shown to promote the development of various carcinomas, 2) that mutations in the PDZ binding motif of LPA1 induces oncogenic transformation , –, , , , and 3) that GIPC plays a tumor suppressor role in breast cancer progression , . Whether and how the interaction of these two proteins is abrogated during cancer progression remains unknown. "
[Show abstract][Hide abstract] ABSTRACT: Lysophosphatidic acid (LPA) mediates diverse cellular responses through the activation of at least six LPA receptors - LPA(1-6,) but the interacting proteins and signaling pathways that mediate the specificity of these receptors are largely unknown. We noticed that LPA(1) contains a PDZ binding motif (SVV) identical to that present in two other proteins that interact with the PDZ protein GIPC. GIPC is involved in endocytic trafficking of several receptors including TrkA, VEGFR2, lutropin and dopamine D2 receptors. Here we show that GIPC binds directly to the PDZ binding motif of LPA(1) but not that of other LPA receptors. LPA(1) colocalizes and coimmunoprecipitates with GIPC and its binding partner APPL, an activator of Akt signaling found on APPL signaling endosomes. GIPC depletion by siRNA disturbed trafficking of LPA(1) to EEA1 early endosomes and promoted LPA(1) mediated Akt signaling, cell proliferation, and cell motility. We propose that GIPC binds LPA(1) and promotes its trafficking from APPL-containing signaling endosomes to EEA1 early endosomes and thus attenuates LPA-mediated Akt signaling from APPL endosomes.
PLoS ONE 11/2012; 7(11):e49227. DOI:10.1371/journal.pone.0049227 · 3.23 Impact Factor
"It has been suggested that these motifs may be associated with the rapid endocytotic rate of LRP1 (Deane et al., 2008). The cytoplasmic tail is phosphorylated on serine and/or tyrosine residues (van der Geer, 2002) and can interact with different adaptor proteins associated with cell signaling, such as disabled-1 (Dab1), FE65 (Klug et al., 2011) and postsynaptic density protein 95 (PSD95) (Trommsdorff et al., 1998; Gotthardt et al., 2000; Herz et al., 2009). Thus, LRP1 has a dual role as a receptor which internalizes its ligands acting like a rapid cargo endocytotic cellular transporter and also as transmembrane cell signaling receptor (Pflanzner et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: Low density lipoprotein receptor-related protein (LRP) belongs to the low-density lipoprotein receptor family, generally recognized as cell surface endocytic receptors, which bind and internalize extracellular ligands for degradation in lysosomes. Neurons require cholesterol to function and keep the membrane rafts stable. Cholesterol uptake into the neuron is carried out by ApoE via LRPs receptors on the cell surface. In neurons the most important are LRP-1 and LRP-2, even it is thought that a causal factor in Alzheimer's disease (AD) is the malfunction of this process which cause impairment intracellular signaling as well as storage and/or release of nutrients and toxic compounds. Both receptors are multifunctional cell surface receptors that are widely expressed in several tissues including neurons and astrocytes. LRPs are constituted by an intracellular (ICD) and extracellular domain (ECD). Through its ECD, LRPs bind at least 40 different ligands ranging from lipoprotein and protease inhibitor complex to growth factors and extracellular matrix proteins. These receptors has also been shown to interact with scaffolding and signaling proteins via its ICD in a phosphorylation-dependent manner and to function as a co-receptor partnering with other cell surface or integral membrane proteins. Thus, LRPs are implicated in two major physiological processes: endocytosis and regulation of signaling pathways, which are both involved in diverse biological roles including lipid metabolism, cell growth processes, degradation of proteases, and tissue invasion. Interestingly, LRPs were also localized in neurons in different stages, suggesting that both receptors could be implicated in signal transduction during embryonic development, neuronal outgrowth or in the pathogenesis of AD.
Frontiers in Physiology 07/2012; 3:269. DOI:10.3389/fphys.2012.00269 · 3.53 Impact Factor
"For example, SFRS15 product binds to carboxyl-terminal domain of the Rpb1 subunit of RNA polymerase II and regulates the transcription , . DAB1 encodes a scaffold protein which interacts with cytoplasmic tails of certain low density lipoprotein (LDL) receptor family proteins that regulate tyrosine kinase signaling and the remodeling of cytoskeleton . LHFP acts as a partner in HMGIC translocations in lipoma . "
[Show abstract][Hide abstract] ABSTRACT: We have derived hESC from biopsied blastomeres of cleavage stage embryos under virtually the same conditions we used for the derivation of hESC lines from inner cell mass of blastocyst stage embryos. Blastomere-derived hESC lines exhibited all the standard characteristics of hESC including undifferentiated proliferation, genomic stability, expression of pluripotency markers and the ability to differentiate into the cells of all three germ layers both in vitro and in vivo. To examine whether hESC lines derived from two developmental stages of the embryo differ in gene expression, we have subjected three blastomere-derived hESC lines and two ICM-derived hESC lines grown under identical culture conditions to transcriptome analysis using gene expression arrays. Unlike previously reported comparisons of hESC lines which demonstrated, apart from core hESC-associated pluripotency signature, significant variations in gene expression profiles of different lines, our data show that hESC lines derived and grown under well-controlled defined culture conditions adopt nearly identical gene expression profiles. Moreover, blastomere-derived and ICM-derived hESC exhibited very similar transcriptional profiles independent of the developmental stage of the embryo from which they originated. Furthermore, this profile was evident in very early passages of the cells and did not appear to be affected by extensive passaging. These results suggest that during derivation process cells which give rise to hESC acquire virtually identical stable phenotype and are not affected by the developmental stage of the starting cell population.
PLoS ONE 10/2011; 6(10):e26570. DOI:10.1371/journal.pone.0026570 · 3.23 Impact Factor
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