Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function

Department of Cardiovascular Science, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, UK.
Blood (Impact Factor: 10.43). 11/2010; 116(22):4646-56. DOI: 10.1182/blood-2010-04-280925
Source: PubMed

ABSTRACT Within the healthy population, there is substantial, heritable, and interindividual variability in the platelet response. We explored whether a proportion of this variability could be accounted for by interindividual variation in gene expression. Through a correlative analysis of genome-wide platelet RNA expression data from 37 subjects representing the normal range of platelet responsiveness within a cohort of 500 subjects, we identified 63 genes in which transcript levels correlated with variation in the platelet response to adenosine diphosphate and/or the collagen-mimetic peptide, cross-linked collagen-related peptide. Many of these encode proteins with no reported function in platelets. An association study of 6 of the 63 genes in 4235 cases and 6379 controls showed a putative association with myocardial infarction for COMMD7 (COMM domain-containing protein 7) and a major deviation from the null hypo thesis for LRRFIP1 [leucine-rich repeat (in FLII) interacting protein 1]. Morpholino-based silencing in Danio rerio identified a modest role for commd7 and a significant effect for lrrfip1 as positive regulators of thrombus formation. Proteomic analysis of human platelet LRRFIP1-interacting proteins indicated that LRRFIP1 functions as a component of the platelet cytoskeleton, where it interacts with the actin-remodeling proteins Flightless-1 and Drebrin. Taken together, these data reveal novel proteins regulating the platelet response.

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    • "LRRFIP1 has been identified as one of the cancer-associated genes (Sjoblom et al., 2006) which promotes cell invasion and metastasis (Arakawa et al., 2010, Ohtsuka et al., 2011, Ariake et al., 2012). In addition, LRRFIP1 isoforms also interact with other proteins, such as Flightless-I (Fli-I), an actin-binding protein (Liu and Yin, 1998, Wilson et al., 1998, Fong and de Couet, 1999), Dishevelled (Dvl), a key molecule in the Wnt signalling cascade (Goodall et al., 2010, Ohtsuka et al., 2011), Toll-like receptor 3 (TLR3), an innate sensor of viral infection (Bagashev et al., 2010) and Drebrin 1 (DBN1), which is involved in the formation of dendritic spines and the stabilisation of tight junctions (Majoul et al., 2007, Goodall et al., 2010). With regards to the mouse isoforms, three different proteins have been reported, two of which, Fli-I leucine-rich repeat associated protein 1 (Flap-1) and Lrrfip1, have been studied. "
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    • "Lrrfip1 has been implicated as a regulator of platelet function [18]. Lrrfip1 also affects the cell cycle, which has been mainly documented in cancer cell proliferation, migration, invasion, and metastasis [19]. "
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