Bone Morphogenetic Protein Receptor Type II C-Terminus Interacts with c-Src

Wong, Wai Keong; Knowles, James A.; Morse, Jane H.

doi:10.1165/rcmb.2005-0103oc

Cited by 93 publications

(94 citation statements)

References 43 publications

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“…Critical regulatory elements in the Id1 promoter include a BMP-responsive region, a serum-responsive region, and a region associated with constitutive expression in breast cancer cells (14)(15)(16)34). Consistent with previous data from noncancerous cells, the present study implicates the crosstalk of Src tyrosine kinase signaling with the BMP-Smad pathway as an additional regulator of Id1 expression in cancer (42)(43)(44)(45). Importantly, this was also associated with a substantial diminution in invasion.…”

Section: Discussionsupporting

confidence: 89%

Regulation of Id1 Expression by Src: Implications for Targeting of the Bone Morphogenetic Protein Pathway in Cancer

et al. 2008

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Deregulated activation of the Src tyrosine kinase and heightened Id1 expression are independent mediators of aggressive tumor biology. The present report implicates Src signaling as a critical regulator of Id1 gene expression. Microarray analyses showed that Id family genes were among the most highly down-regulated by incubation of A549 lung carcinoma cells with the small-molecule Src inhibitor AZD0530. Id1 transcript and protein levels were potently reduced in a dose-dependent manner concomitantly with the reduction of activated Src levels. These effects were conserved across a panel of lung, breast, prostate, and colon cancer cell lines and confirmed by the ability of PP2, Src siRNA, and Srcblocking peptides to suppress Id1 expression. PP2, AZD0530, and dominant-negative Src abrogated Id1 promoter activity, which was induced by constitutively active Src. The Srcresponsive region of the Id1 promoter was mapped to a region 1,199 to 1,360 bps upstream of the translation start site and contained a Smad-binding element. Src was also required for bone morphogenetic protein-2 (BMP-2)-induced Id1 expression and promoter activity, was moderately activated by BMP-2, and complexed with Smad1/5. Conversely, Src inhibitors blocked Smad1/5 nuclear translocation and binding to the Src-responsive region of the Id1 promoter. Consistent with a role for Src and Id1 in cancer cell invasion, Src inhibitors and Id1 siRNA decreased cancer cell invasion, which was increased by Id1 overexpression. Taken together, these results reveal that Src positively interacts with the BMP-Smad-Id pathway and provide new ways for targeted inhibition of Id1. [Cancer Res 2008;68(7):2250-8]

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Section: Discussionsupporting

confidence: 89%

Regulation of Id1 Expression by Src: Implications for Targeting of the Bone Morphogenetic Protein Pathway in Cancer

et al. 2008

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“…The second regulator of STAT3 activation is the Src pathway [58]. Src has been shown to be implicated in PAH [5,31] and in the activation of STAT3 in human PAH-PASMCs [5]. Although the implication of Src in STAT3 activation in human PAH-PASMCs has not been reassessed in the present study, we showed that Src is activated in the distal pulmonary arteries of both MCT and sugen rats, confirming our previous findings in humans.…”

Section: Pulmonary Vascular Diseasesupporting

confidence: 90%

“…PLB reverses the activation of pathophysiological pathways affected by the activation of the STAT3/NFAT axis In PAH-PASMCs, STAT3/NFAT-mediated proliferation [4,31] has been linked with the downregulation of voltage-gated K + (Kv) channels [32,33], resulting in membrane depolarisation [31,33], the opening of voltage-dependent calcium channels, and an increase in [Ca 2+ ] i [4,31,34]. Using whole-cell patch clamping, we demonstrated that PLB (48 h) restores the decrease in total K + current density observed in PAH-PASMCs ( fig.…”

Section: Plb Decreases the Stat3/nfat Axis Activation In Pahpasmcsmentioning

confidence: 99%

Plumbagin reverses proliferation and resistance to apoptosis in experimental PAH

et al. 2012

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Like cancer, pulmonary arterial hypertension (PAH) is characterised by a proproliferative and anti-apoptotic phenotype. In PAH, pulmonary artery smooth muscle cell (PASMC) proliferation is enhanced and apoptosis suppressed. The sustainability of this phenotype requires the activation of pro-survival transcription factors, such as signal transducer and activator of transcription (STAT)3 and nuclear factor of activated T-cells (NFAT). There are no drugs currently available that are able to efficiently and safely inhibit this axis. We hypothesised that plumbagin (PLB), a natural organic compound known to block STAT3 in cancer cells, would reverse experimental pulmonary hypertension.Using human PAH-PASMC, we demonstrated in vitro that PLB inhibits the activation of the STAT3/NFAT axis, increasing the voltage-gated K + current bone morphogenetic protein receptor type II (BMPR2), and decreasing intracellular Ca 2+ contentration ([Ca 2+ ] i ), rho-associated coiledcoil containing protein kinase (ROCK)1 and interleukin (IL)-6, contributing to the inhibition of PAH-PASMC proliferation and resistance to apoptosis (proliferating cell nuclear antigen (PCNA), TUNEL, Ki67 and anexine V). In vivo, PLB oral administration decreases distal pulmonary artery remodelling, mean pulmonary artery pressure and right ventricular hypertrophy without affecting systemic circulation in both monocrotaline-and sugen/chronic hypoxia-induced PAH in rats.This study demonstrates that the STAT3/NFAT axis can be therapeutically targeted by PLB in human PAH-PASMC and experimental PAH rat models. Thus, PLB could be considered a specific and attractive future therapeutic strategy for PAH.

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“…These analyses suggest that the penetrance may be determined by subtle genetic differences in the known HPAH pathways, in particular the G-proteincoupled receptor pathways because that pathway was present in the final signature and in the GSEA. These findings are not surprising because G protein-coupled receptors have been implicated in pulmonary vasoconstriction pathways in several studies (28)(29)(30)(31)(32)(33)(34)(35).…”

Section: Discussionmentioning

confidence: 78%

Connectivity Map Analysis of Nonsense-Mediated Decay–Positive BMPR2-Related Hereditary Pulmonary Arterial Hypertension Provides Insights into Disease Penetrance

Flynn

Zheng²,

Ling

et al. 2012

Am J Respir Cell Mol Biol

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The molecular mechanisms underlying the reduced penetrance seen in the nonsense-mediated decay-positive (NMD1) BMPR2 mutationassociated hereditary pulmonary arterial hypertension (HPAH) remain unknown. We reasoned that the cellular and genetic mechanisms behind this phenomenon could be uncovered by combining expression profiling with Connectivity Map (cMap) analysis. Cultured lymphocytes from 10 patients with HPAH and 10 matched familial control subjects, all with NMD1 BMPR2 mutations, were subjected to expression analysis. For each group, the expression data were combined before analysis. This generated a signature of 23 up-regulated and 12 down-regulated genes in patients with HPAH compared with control subjects (the "PAH penetrance signature"). Although gene set enrichment analysis of this signature was not uniquely informative, cMap analysis identified drugs with expression signatures similar to the PAH penetrance signature. Several of these drugs were predicted to influence reactive oxygen species (ROS) formation. This hypothesis was tested and confirmed in the same cells initially subjected to the expression analysis using quantitative biochemical detection of ROS concentration. We conclude that expression of the PAH penetrance signature represents an increased risk of developing clinical HPAH and that ROS formation may play a role in pathogenesis of HPAH. These results provide the first molecular insights into NMD1 BMPR2 related HPAH penetrance and highlight the potential utility of cMap analyses in pulmonary research.Keywords: hereditary pulmonary arterial hypertention; ROS; connectivity map; expression signature; BMPR2 Pulmonary arterial hypertension (PAH) is a progressive, fatal disease, and most patients with PAH have a poor prognosis despite standard-of-care therapies (1). PAH is characterized by vascular remodeling of the distal pulmonary arteries (100-200 mM in size) via smooth muscle hypertrophy and intimal endothelial cell proliferation, effectively decreasing the surface area of the pulmonary vasculature (2, 3). The resulting increase in pulmonary vascular resistance leads to the failure of a progressively overloaded right ventricle and, eventually, death. The heritable form of PAH (HPAH) is usually (.80% of the time) due to germline mutations in the Bone Morphogenetic Protein Receptor 2 (BMPR2) (4-7), whereas 5 to 25% of patients diagnosed as having idiopathic (I) PAH have a detectable germline mutation in BMPR2 as well (5,(12)(13)(14)(15).In HPAH, BMPR2 mutations can produce stable transcripts or premature termination codons, resulting in the mutated transcript being rapidly degraded through the nonsense-mediated decay (NMD) pathway (8). NMD is an mRNA surveillance system that degrades transcripts containing premature termination codons to prevent translation of unnecessary or harmful transcripts (9). Thus, patients with PAH with NMD-positive (NMD1) BMPR2 mutations have disease due to haploinsufficiency, whereas patients whose mutations are NMD negative (NMD2) may have disease due to a dominan...

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Bone Morphogenetic Protein Receptor Type II C-Terminus Interacts with c-Src

Cited by 93 publications

References 43 publications

Regulation of Id1 Expression by Src: Implications for Targeting of the Bone Morphogenetic Protein Pathway in Cancer

Regulation of Id1 Expression by Src: Implications for Targeting of the Bone Morphogenetic Protein Pathway in Cancer

Plumbagin reverses proliferation and resistance to apoptosis in experimental PAH

Connectivity Map Analysis of Nonsense-Mediated Decay–Positive BMPR2-Related Hereditary Pulmonary Arterial Hypertension Provides Insights into Disease Penetrance

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