Carl Henrik Heldin

..Lowering the tumour IFP with specific signal-transduction antagonists might be a useful approach to improving anticancer drug efficacy...

..Moreover, delivery of PDGF-CC enhanced postischemic revascularization of the heart and limb. Modulating the activity of PDGF-CC may provide novel opportunities for treating ischemic diseases...

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..The EMT program has certain similarities with the stem cell program. Inducers and effectors of EMT are interesting targets for the development of improved diagnosis, prognosis and therapy of cancer...

..Herein, we focus on the diversification of the transforming growth factor-beta (TGF-beta) pathway -- one of the fundamental and versatile metazoan signal transduction engines...

..Besides differential receptor binding, the duration of TGF-beta signaling is an important specificity determinant for signaling responses. TGF-beta/ALK1-induced Smad1/5 phosphorylation in ECs occurs transiently...

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..The Smad function has been shown to be perturbed in certain diseases such as cancer...

..The aim of this review is to summarize some of the recent findings on the mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition...

..With a focus on excellence, calls for both young and experienced scientists and an average budget of \[euro]1 billion per year, the ERC will have the opportunity to give basic research in Europe a significant boost...

..This review discusses structural and functional properties of PDGF and PDGF receptors, the mechanism whereby PDGF exerts its cellular effects, and the role of PDGF in normal and diseased tissues...

..Thus, antagonists of several signaling pathways have potential clinical utility. Several such compounds are currently used or are in clinical trials; others are currently being analyzed in animal models...

..In conclusion, YY1 represses Smad transcriptional activities in a gene-specific manner and thus regulates cell differentiation induced by TGF-beta superfamily pathways...

..Moreover, ectopically expressed Smad7 enhanced the coimmunoprecipitation of HA-MKK3 and Flag-p38, supporting the notion that Smad7 may act as a scaffolding protein and facilitate TAK1- and MKK3-mediated activation of p38...

..In conclusion, Gab1 plays a selective role in the regulation of the mitogen-activated protein kinases Erk and p38 downstream of the PDGF beta-receptor, and contributes to cytoskeletal reorganization and chemotaxis in response to PDGF...

..These data suggest that oligo-ubiquitination positively regulates Smad4 function, whereas poly-ubiquitination primarily occurs in unstable cancer mutants and leads to protein degradation...

..Collectively, these data indicate that TGF-beta-induced membrane ruffles occur via Rho GTPase-dependent pathways, whereas long-term effects require cooperation between Smad and Rho GTPase signaling pathways...

..Our findings support a model whereby an activating point mutation results in a deregulated PDGFRbeta with oncogenic predisposition...

..These observations propose a novel role for Smad7 in TGF-beta-dependent activation of Rho GTPases...

..The TGFbeta1-dependent inhibition of DNA repair was reversed by ectopic overexpression of Rad51. Therefore, TGFbeta can promote DNA instability through down-regulation of Rad51 and inhibition of DNA repair...

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..Thus, our data suggest that competition between ubiquitination and acetylation of overlapping lysine residues constitutes a novel mechanism to regulate protein stability...

..Thus, our results show that BRCA2 and Smad3 form a complex and synergize in regulation of transcription...

..Collectively, these results suggest that the ligand-induced association of NHERF PDZ domain with the PDGF receptor tyrosine kinase controls the extent of cytoskeleton reorganization in response to PDGF...

..Thus, SHP-2 appears to play an important role in modulating phosphorylation of Y771, thereby controlling RasGAP recruitment and Ras/MAP kinase signaling in the heterodimeric configuration of the PDGF receptors...

..Such mechanisms of down-regulation of TGF-beta signaling may be critical for proper physiological response to this pathway...

..Thus, loss of TC-PTP specifically redirects the PDGF beta-receptor toward rapid recycling, which is the first evidence of differential trafficking of PDGF receptor family members...

..In conclusion, TGFβ induces expression of Smad7, Smurf2, and SIK1, the products of which physically and functionally interlink to control the activity of this pathway...

..These findings indicate that allosteric inhibition of the PDGF beta-receptor by its C-terminal tail is one of the mechanisms involved in keeping the receptor inactive in the absence of ligand...

..Interestingly, K190R-mutated HAS2 formed dimers with wt HAS2 and quenched the activity of wt HAS2, thus demonstrating a functional role of the dimeric configuration...

..This network of signaling/transcription factors that work sequentially to establish EMT suggests that combinatorial detection of these proteins could serve as a new tool for EMT analysis in cancer patients...

..Our data imply that Smad7 plays a crucial role upstream of ATM and p53 to protect the genome from insults evoked by extracellular stress...

..Moreover, the Smad7-APC complex links the TGFβ type I receptor to the microtubule system to regulate directed cellular extension and migratory responses evoked by TGFβ...

..In conclusion, JNK is a critical component downstream of PI 3-kinase that may be involved in PDGF-stimulated chemotaxis presumably by modulating the integrity of focal adhesions by phosphorylating its components...

..Thus, our results identify ADP-ribosylation of Smad proteins by PARP-1 as a key step in controlling the strength and duration of Smad-mediated transcription...

..In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors...

..Thus, p21 is a common target of all TGF-beta superfamily pathways. However, the ability of TGF-beta superfamily members to induce cell growth arrest depends on the regulation of additional gene targets...

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..Our data suggest that Alix inhibits down-regulation of PDGFRbeta by modulating the interaction between c-Cbl and the receptor, thereby affecting the ubiquitination of the receptor...

..Simultaneous targeting of VEGFR and PDGFR kinase activity may be a useful strategy to decrease tumor IFP, but the timing of the inhibitors should be carefully determined...

..Interestingly, PDGFRbeta(Y857F) was unable to mediate PDGF-BB-induced mitogenic signaling, whereas it could elicit a chemotactic response...

..Our observations suggest that hyaluronan suppresses PDGF beta-receptor activation by recruiting a CD44-associated tyrosine phosphatase to the receptor...

..The data propose that HMGA2 acts in a gene-specific manner to orchestrate the transcriptional network necessary for the EMT program...

..Thus, coactivator-mediated acetylation of receptor-activated Smad molecules could represent a novel way to regulate TGFbeta signaling...

..Because the CTCF-Smad complex is not essential for the chromatin insulator function of the H19 ICR, we propose that it can play a role in chromatin cross-talk organized by the H19 ICR...

..Thus, TGFbeta1/Smad3 suppresses BRCA1-dependent DNA repair in response to a DNA damaging agent...

..We establish an intimate involvement of Notch signaling in the epithelial cytostatic response to TGF-beta...

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..7 after LPS treatment. In conclusion, polyubiquitination of TAK1 is correlated with activation of TAK1 and is essential for activation of NF-κB signaling downstream of several receptors...

..We conclude that the ERK MAPK and PI3K signalling pathways are necessary for the regulation of hyaluronan synthesis by PDGF-BB, and that prevention of its binding to CD44 inhibits PDGF-BB-induced cell growth...

..A short peptide representing the minimal interaction domain in Smad3 effectively competes with Smad3 association to exportin 4 and blocks nuclear export of Smad3 in vivo. We thus delineate a novel nuclear export pathway for Smad3...

..Conversely, an EGF receptor inhibitor reduced the proliferation of these cells. Our data indicate that endogenous Smad7 regulates neural stem/progenitor cell proliferation in a TGF-beta- and BMP-independent manner...

..Loss of endogenous SIK results in enhanced gene responses of the fibrotic and cytostatic programs of TGFbeta. We thus identify in SIK a negative regulator that controls TGFbeta receptor turnover and physiological signaling...

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..Interestingly, LPS treatment reverted the apoptotic phenotype in the mutant cells. Taken together, the observed phenotype highlights a prominent role for Smad7 in development and in regulating the immune system's response to TGF-beta...

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..In conclusion, our results suggest that growth factors induce membrane lipid synthesis via the activation SREBP and PI3K...

..Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6...

..These observations suggest that LAR reduces the basal c-Abl activity thereby allowing for PDGF β-receptor kinase activation...

..Here we present some of the current mechanisms that mediate the process of EMT and discuss their relevance to cancer progression...

..In addition, the fetal blood vessel compartment of the labyrinth was completely disorganized...

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..We discuss mechanisms and models that aim at explaining the coordination between several components of the signaling network downstream of the TGF-beta signal...

..Accordingly, LKB1 negatively regulates TGFβ gene responses and epithelial-mesenchymal transition. Thus, LKB1 and LIP1 provide negative control of TGFβ signaling...

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..Two rounds of WGD (2R-WGD) occurred at the base of vertebrates, giving rise to an enormous wave of genetic novelty, but a systematic analysis of functional consequences of this event has not yet been performed...

..Thus, Meox2 is primarily involved in the TGF-beta tumor suppressor pathway...

..In conclusion, cross-talk with other PDGFRβ-induced signaling pathways is important for fine-tuning of the pattern of Erk1/2 activation...

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..Thus, the substrate-mimetic peptide is a new type of specific inhibitor of the TGFbeta signaling in vivo...

..This allowed us to investigate, in an orthotopic tumor model, the role of increased stromal PDGFR-beta signaling in tumor-stroma interactions...

..The Gray horse provides a notable example of how humans have cherry-picked mutations with favorable phenotypic effects in domestic animals...

..Signaling is modulated by negative-feedback regulation via inhibitory Smads. We review here the mechanisms of TGFbeta signal transduction in metazoans and emphasize events crucial for embryonic development...

..In conclusion, MKP3 is an important regulator of PDGF-induced Erk phosphorylation acting in both a rapid positive feed-forward and a later negative feed-back loop...

..Thus, Id genes sense Smad signals and create a permissive or refractory nuclear environment that defines decisions of cell fate and proliferation...

..Thus, Arg-462 and Cys-463, which are in proximity of the C-terminal serine residues, contribute to recognition and phosphorylation of the C terminus of Smad2 by type I TGFbeta receptor...

..We confirmed this hypothesis with a second injury model, cutaneous wound healing, where we observed earlier proliferation and formation of granulation tissue in D849N-mutant mice...

..Moreover, signaling involving the Rho GTPases was defective in KO cells. In summary, our observations suggest that the Nck adapters are needed for signaling to Rho GTPases and actin dynamics downstream of the PDGFbeta receptor...

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..Our results suggest that 1,25(OH)2-vitamin D3 modulates in opposite ways the effects of BMP7 and TGFbeta1 on osteoblast differentiation...

..The present review discusses the development and possible clinical use of antagonsts for PDGF and TGF-beta...

..Thus, TGFbeta1-dependent phosphorylation of TFII-I may modulate TGFbeta signaling at the transcriptional level...

..In conclusion, our study identifies inhibition of PDGF signaling in tumor stroma as a novel, possibly general strategy for enhancement of the therapeutic effects chemotherapy...

..The results implicate that TGF-beta1 affects the function of the mitochondria and may be of significance for the understanding of the proapoptotic effect of TGF-beta1 in these cells...

..The study thus validates STI571 for combination treatment to enhance the therapeutic index of EPO906 in particular and, possibly, of chemotherapeutics in general...

..Our findings thus demonstrate that paracrine PDGF production stimulates pericyte recruitment to tumor vessels and suggest that pericyte abundance influences tumor cell apoptosis and tumor growth...

..New findings demonstrate that transcriptional intermediary factor 1gamma (TIF1gamma) also can bind to R-Smads, as an alternative to Smad4, and mediate different transcriptional effects...

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..We suggest that Sts-1 and Sts-2 represent a novel class of Ub-binding proteins that regulate RTK endocytosis and control growth factor-induced cellular functions...

..However, the TGF-beta-induced epithelial to mesenchymal transdifferentiation was found to require an intact L45 loop and is likely to be dependent on the Smad pathways...

..001). These results suggest that the ability of high SS to inhibit arterial wall thickening in vivo may be related to enhanced activation of PDGFRalpha in SMCs by PDGF isoforms secreted by the endothelium...