Novel splice variants derived from the receptor tyrosine kinase superfamily are potential therapeutics for rheumatoid arthritis

Pei, Jin; Zhang, Juan; Sumariwalla, Percy F.; Ni, Irene; Jorgensen, Brett; Crawford, Damian; Phillips, Suzanne; Feldmann, Marc; Shepard, H. Michael; Paleolog, Ewa

doi:10.1186/ar2447

Cited by 36 publications

(17 citation statements)

References 68 publications

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“…Multiple variants of human sFlt-1 have been identified [16]. Primer pairs for PCR were designed that are unique to the mRNA of the four known human sFlt-1 Variants.…”

Section: Resultsmentioning

confidence: 99%

AUF1-RGG peptides up-regulate the VEGF antagonist, soluble VEGF receptor-1 (sFlt-1)

2013

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The macrophage is essential to the innate immune response, but also contributes to human disease by aggravating inflammation. Under severe inflammation, macrophages and other immune cells over-produce immune mediators, including vascular endothelial growth factor (VEGF). The VEGF protein stimulates macrophage activation and induces macrophage migration. A natural inhibitor of VEGF, the soluble VEGF receptor (sFlt-1) is also produced by macrophages and sFlt-1 has been used clinically to block VEGF. In macrophages, we have shown that the mRNA regulatory protein AUF1/hnRNP D represses VEGF gene expression by inhibiting translation of AURE-regulated VEGF mRNA. Peptides (AUF1-RGG peptides) that are modeled on the arginine- glycine-glycine (RGG) motif in AUF1 also block VEGF expression. This report shows that the AUF1-RGG peptides reduce two other AURE-regulated genes, TNF and GLUT1. Three alternative splice variants of sFlt-1 contain AURE in their 3′UTR, and in an apparent paradox, AUF1-RGG peptides stimulate expression of these three sFlt-1 variants. The AUF1-RGG peptides likely act by distinct mechanisms with complimentary effects to repress VEGF gene expression and over-express the endogenous VEGF blocking agent, sFlt-1. The AUF1-RGG peptides are novel reagents that reduce VEGF and other inflammatory mediators, and may be useful tools to suppress severe inflammation.

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“…Multiple variants of human sFlt-1 have been identified [16]. Primer pairs for PCR were designed that are unique to the mRNA of the four known human sFlt-1 Variants.…”

Section: Resultsmentioning

confidence: 99%

AUF1-RGG peptides up-regulate the VEGF antagonist, soluble VEGF receptor-1 (sFlt-1)

2013

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“…DDR1a, DDR1b, and DDR1c are full-length functional receptors, and DDR1d and DDR1e are truncated or kinase-inactive receptors (10,12). Two additional secreted splice variants of DDR1 have also been identified (13). DDR1b and DDR1c contain an additional 37 residues within the intracellular juxtamembrane (IJXM) region.…”

Section: Ddr Structurementioning

confidence: 99%

Discoidin Domain Receptors: Unique Receptor Tyrosine Kinases in Collagen-mediated Signaling

Valiathan

Arkwright

et al. 2013

Journal of Biological Chemistry

194

180

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The discoidin domain receptors (DDRs) are receptor tyrosine kinases that recognize collagens as their ligands. DDRs display unique structural features and distinctive activation kinetics, which set them apart from other members of the kinase superfamily. DDRs regulate cell-collagen interactions in normal and pathological conditions and thus are emerging as major sensors of collagen matrices and potential novel therapeutic targets. New structural and biological information has shed light on the molecular mechanisms that regulate DDR signaling, turnover, and function. This minireview provides an overview of these areas of DDR research with the goal of fostering further investigation of these intriguing and unique receptors. The discoidin domain receptor (DDR)2 family comprises two distinct members, DDR1 and DDR2, which were initially discovered in the early 1990s and characterized as receptor tyrosine kinases (RTKs) based on the presence of a catalytic kinase domain (KD) (1-7). Subsequently, collagens were identified as ligands for DDRs (8), thus establishing the unique characteristic of these receptors among other members of the RTK superfamily. Upon collagen binding, DDRs undergo tyrosine autophosphorylation with distinctive activation kinetics, which elicits genetic and cellular programs that regulate a variety of cell-collagen interactions. Despite their unique characteristics, the biochemical and cellular mechanisms by which DDRs mediate their multiple biological effects remain poorly defined. This minireview provides an overview of current information on DDR structure, regulation, and signaling. For information on specific DDR biological functions in processes such as cell adhesion, migration, and invasion over collagen matrices and their role in normal and pathological processes, the reader is directed to the following recent reviews (9 -11) DDR StructureThe DDR1 subfamily is composed of five membrane-anchored isoforms, and the DDR2 subfamily is represented by a single protein. The five DDR1 isoforms are generated by alternative splicing. DDR1a, DDR1b, and DDR1c are full-length functional receptors, and DDR1d and DDR1e are truncated or kinase-inactive receptors (10, 12). Two additional secreted splice variants of DDR1 have also been identified (13). DDR1b and DDR1c contain an additional 37 residues within the intracellular juxtamembrane (IJXM) region. With the exception of the two secreted DDR1 isoforms, all DDRs are single-pass type I transmembrane glycoproteins that are characterized by the presence of six distinct protein domains: a discoidin (DS) domain, a DS-like domain, an extracellular juxtamembrane (EJXM) region, a transmembrane (TM) segment, a long IJXM region, and an intracellular KD (Fig. 1A). The presence of the N-terminal DS and DS-like domains is the defining feature of the DDR RTK subfamily. The DS domain exhibits high homology to a protein module originally identified in proteins from Dictyostelium discoideum (14). In this organism, the DS domain functions as a galactose-binding lectin, whic...

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“…: VEGFR1, HER-2, Met) (He et al, 1999; Scott et al, 1993; Tiran et al, 2008), but whether natural ectodomains are a general RTK feature remains unclear. In many cases the mechanism underlying the generation of sdRTK isoforms is unknown, with protease cleavage and ectodomain shedding, alternative splicing, or IPA as proposed mechanisms (Heaney and Golde, 1998; Jin et al, 2008; Swendeman et al, 2008). Enhanced RTK signaling is a driving force in many human malignancies (Lemmon and Schlessinger, 2010), and gaining further insight into regulation of these pathways might result in treatment opportunities.…”

Section: Introductionmentioning

confidence: 99%

Induction of Antagonistic Soluble Decoy Receptor Tyrosine Kinases by Intronic PolyA Activation

et al. 2011

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SUMMARY Alternative intronic polyadenylation (IPA) can generate truncated protein isoforms with significantly altered functions. Here, we describe 31 dominant-negative, secreted variant isoforms of receptor tyrosine kinases (RTKs) that are produced by activation of intronic poly(A) sites. We show that blocking U1-snRNP can activate IPA, indicating a larger role for U1-snRNP in RNA surveillance. Moreover, we report the development of an antisense-based method to effectively and specifically activate expression of individual soluble decoy RTKs (sdRTKs) to alter signaling, with potential therapeutic implications. In particular, a quantitative switch from signal transducing full-length vascular endothelial growth factor receptor-2 (VEGFR2/KDR) to a dominant-negative sKDR results in a strong anti-angiogenic effect both on directly targeted cells and on naïve cells exposed to conditioned media, suggesting a role for this approach in interfering with angiogenic paracrine and autocrine loops.

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Novel splice variants derived from the receptor tyrosine kinase superfamily are potential therapeutics for rheumatoid arthritis

Cited by 36 publications

References 68 publications

AUF1-RGG peptides up-regulate the VEGF antagonist, soluble VEGF receptor-1 (sFlt-1)

AUF1-RGG peptides up-regulate the VEGF antagonist, soluble VEGF receptor-1 (sFlt-1)

Discoidin Domain Receptors: Unique Receptor Tyrosine Kinases in Collagen-mediated Signaling

Induction of Antagonistic Soluble Decoy Receptor Tyrosine Kinases by Intronic PolyA Activation

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