ArticleThe Journal of biological chemistry2008
Molecular dissection of the human alpha2-macroglobulin subunit reveals domains with antagonistic activities in cell signaling.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 52 citations in OpenAlex.
- Review
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- c-Abl Tyrosine Kinase-Mediated Neuronal Apoptosis in Subarachnoid Hemorrhage by Modulating the LRP-1-Dependent Akt/GSK3β Survival Pathway.Journal of molecular neuroscience : MN · 2021Article
- Remission of Diabetes Following Bariatric Surgery: Plasma Proteomic Profiles.Journal of clinical medicine · 2021Article
- Schwann cell interactions during the development of the peripheral nervous system.Developmental neurobiology · 2021Review
- From the low-density lipoprotein receptor-related protein 1 to neuropathic pain: a potentially novel target.Pain reports · 2021Review
- A soluble derivative of PrPThe Journal of biological chemistry · 2020Article
- Proteomic analysis of human epileptic neocortex predicts vascular and glial changes in epileptic regions.PloS one · 2018Article
- Neuron-derived transthyretin modulates astrocytic glycolysis in hormone-independent manner.Oncotarget · 2017Article
- Identification of the protective mechanisms of Lactoferrin in the irradiated salivary gland.Scientific reports · 2017Article
- LRP1-Dependent BMPER Signaling Regulates Lipopolysaccharide-Induced Vascular Inflammation.Arteriosclerosis, thrombosis, and vascular biology · 2017Article
- Ionotropic glutamate receptors activate cell signaling in response to glutamate in Schwann cells.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
- Neuroserpin Attenuates HJournal of molecular neuroscience : MN · 2017Article
- Low-Density Lipoprotein Receptor-Related Protein-1 Signaling in Angiogenesis.Frontiers in cardiovascular medicine · 2017Review
- Transthyretin provides trophic support via megalin by promoting neurite outgrowth and neuroprotection in cerebral ischemia.Cell death and differentiation · 2016Article
- The activities of LDL Receptor-related Protein-1 (LRP1) compartmentalize into distinct plasma membrane microdomains.Molecular and cellular neurosciences · 2016Article
- LRP1 Regulates Retinal Angiogenesis by Inhibiting PARP-1 Activity and Endothelial Cell Proliferation.Arteriosclerosis, thrombosis, and vascular biology · 2016Article
- Mesenchymal Stromal Cells Promote Axonal Outgrowth Alone and Synergistically with Astrocytes via tPA.PloS one · 2016Article
- The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration.Journal of cell science · 2015Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
alpha(2)-Macroglobulin (alpha(2)M) is a plasma protease inhibitor, which reversibly binds growth factors and, in its activated form, binds to low density lipoprotein receptor-related protein (LRP-1), an endocytic receptor with cell signaling activity. Because distinct domains in alpha(2)M are responsible for its various functions, we hypothesized that the overall effects of alpha(2)M on cell physiology reflect the integrated activities of multiple domains, some of which may be antagonistic. To test this hypothesis, we expressed the growth factor carrier site and the LRP-1 recognition domain (RBD) as separate GST fusion proteins (FP3 and FP6, respectively). FP6 rapidly and robustly activated Akt and ERK/MAP kinase in Schwann cells and PC12 cells. This response was blocked by LRP-1 gene silencing or by co-incubation with the LRP-1 antagonist, receptor-associated protein. The activity of FP6 also was blocked by mutating Lys(1370) and Lys(1374), which precludes LRP-1 binding. FP3 blocked activation of Akt and ERK/MAP kinase in response to nerve growth factor-beta (NGF-beta) but not FP6. In PC12 cells, FP6 promoted neurite outgrowth and expression of growth-associated protein-43, whereas FP3 antagonized the same responses when NGF-beta was added. The ability of FP6 to trigger LRP-1-dependent cell signaling in PC12 cells was reproduced by the 18-kDa RBD, isolated from plasma-purified alpha(2)M by proteolysis and chromatography. We propose that the effects of intact alpha(2)M on cell physiology reflect the degree of penetration of activities associated with different domains, such as FP3 and FP6, which may be regulated asynchronously by conformational change and by other regulatory proteins in the cellular microenvironment.
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