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Briefings in Functional Genomics and Proteomics (1)
PLoS ONE (1)
Finney, Greg L. (2)
Chan, Maia M. (1)
Gilligan, Diana M. (1)
Hirenallur-S, Dinesh K. (1)
Iritani, Brian M. (1)
Kline, Kelli G. (1)
MacCoss, Michael (1)
Park, Heon (1)
Ramirez, Julita A. (1)
Rynes, Eric (1)
Tsang, Mark (1)
Wooden, Jason M. (1)
Wu, Christine C. (1)
Year of Publication
Quantitative strategies to fuel the merger of discovery and hypothesis-driven shotgun proteomics
Kline, Kelli G.
Wu, Christine C.
Briefings in Functional Genomics and Proteomics
The ultimate goal of most shotgun proteomic pipelines is the discovery of novel biomarkers to direct the development of quantitative diagnostics for the detection and treatment of disease. Differential comparisons of biological samples identify candidate peptides that can serve as proxys of candidate proteins. While these discovery approaches are robust and fairly comprehensive, they have relatively low throughput. When merged with targeted mass spectrometry, this pipeline can fuel hypothesis-driven studies and the development of novel diagnostics and therapeutics.
quantitative shotgun proteomics; biomarker discovery; targeted mass spectrometry; human tissue
Hematopoietic Protein-1 Regulates the Actin Membrane Skeleton and Membrane Stability in Murine Erythrocytes
Chan, Maia M.
Wooden, Jason M.
Gilligan, Diana M.
Hirenallur-S, Dinesh K.
Ramirez, Julita A.
Iritani, Brian M.
Hematopoietic protein-1 (Hem-1) is a hematopoietic cell specific member of the WAVE (Wiskott-Aldrich syndrome verprolin-homologous protein) complex, which regulates filamentous actin (F-actin) polymerization in many cell types including immune cells. However, the roles of Hem-1 and the WAVE complex in erythrocyte biology are not known. In this study, we utilized mice lacking Hem-1 expression due to a non-coding point mutation in the Hem1 gene to show that absence of Hem-1 results in microcytic, hypochromic anemia characterized by abnormally shaped erythrocytes with aberrant F-actin foci and decreased lifespan. We find that Hem-1 and members of the associated WAVE complex are normally expressed in wildtype erythrocyte progenitors and mature erythrocytes. Using mass spectrometry and global proteomics, Coomassie staining, and immunoblotting, we find that the absence of Hem-1 results in decreased representation of essential erythrocyte membrane skeletal proteins including α- and β- spectrin, dematin, p55, adducin, ankyrin, tropomodulin 1, band 3, and band 4.1. Hem1−/− erythrocytes exhibit increased protein kinase C-dependent phosphorylation of adducin at Ser724, which targets adducin family members for dissociation from spectrin and actin, and subsequent proteolysis. Increased adducin Ser724 phosphorylation in Hem1−/− erythrocytes correlates with decreased protein expression of the regulatory subunit of protein phosphatase 2A (PP2A), which is required for PP2A-dependent dephosphorylation of PKC targets. These results reveal a novel, critical role for Hem-1 in the homeostasis of structural proteins required for formation and stability of the actin membrane skeleton in erythrocytes.
Results 1-2 (2)
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