Biomedical subjects

C H Heldin

Publications and source records attributed to C H Heldin.

At least 91 records · Page 5Linked to original sources

PubMed1997

A novel GTPase-activating protein for Rho interacts with a PDZ domain of the protein-tyrosine phosphatase PTPL1.

PTPL1 is an intracellular protein-tyrosine phosphatase that contains five PDZ domains. Here, we present the cloning of a novel 150-kDa protein, the four most C-terminal amino acid residues of which specifically interact with the fourth PDZ domain of PTPL1. The molecule contains a GTPase-activating protein (GAP) domain, a cysteine-rich, putative Zn2+- and diacylglycerol-binding domain, and a region of sequence homology to the product of the Caenorhabditis elegans gene ZK669.1a. The GAP domain is active on Rho, Rac, and Cdc42 in vitro but with a clear preference for Rho; we refer to the molecule as PTPL1-associated RhoGAP 1, PARG1. Rho is inactivated by GAPs, and protein-tyrosine phosphorylation has been implicated in Rho signaling. Therefore, a complex between PTPL1 and PARG1 may function as a powerful negative regulator of Rho signaling, acting both on Rho itself and on tyrosine phosphorylated components in the Rho signal transduction pathway.

Amino Acid Sequence↗

PubMed1997

Identification of a 190-kDa vascular endothelial growth factor 165 cell surface binding protein on a human glioma cell line.

Vascular endothelial growth factor (VEGF) is an angiogenesis factor for which two signaling protein tyrosine kinase receptors, Flt1 and KDR, have been identified. We describe here a 190-kDa component present on a human glioma cell line that binds VEGF165 with high affinity. In contrast, VEGF121 is bound only with low affinity, suggesting that the C-terminal part of VEGF165 is important for interaction with the 190-kDa component. No internalization or stimulation of tyrosine phosphorylation was recorded after ligand binding to the 190-kDa component, suggesting that it may not be directly involved in signaling; its function may be to present ligand or stabilize ligand binding to signaling receptors.

Amidohydrolases↗

PubMed1997

TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4.

Smad family members are newly identified essential intracellular signalling components of the transforming growth factor-beta (TGF-beta) superfamily. Smad2 and Smad3 are structurally highly similar and mediate TGF-beta signals. Smad4 is distantly related to Smads 2 and 3, and forms a heteromeric complex with Smad2 after TGF-beta or activin stimulation. Here we show that Smad2 and Smad3 interacted with the kinase-deficient TGF-beta type I receptor (TbetaR)-I after it was phosphorylated by TbetaR-II kinase. TGF-beta1 induced phosphorylation of Smad2 and Smad3 in Mv1Lu mink lung epithelial cells. Smad4 was found to be constitutively phosphorylated in Mv1Lu cells, the phosphorylation level remaining unchanged upon TGF-beta1 stimulation. Similar results were obtained using HSC4 cells, which are also growth-inhibited by TGF-beta. Smads 2 and 3 interacted with Smad4 after TbetaR activation in transfected COS cells. In addition, we observed TbetaR-activation-dependent interaction between Smad2 and Smad3. Smads 2, 3 and 4 accumulated in the nucleus upon TGF-beta1 treatment in Mv1Lu cells, and showed a synergistic effect in a transcriptional reporter assay using the TGF-beta-inducible plasminogen activator inhibitor-1 promoter. Dominant-negative Smad3 inhibited the transcriptional synergistic response by Smad2 and Smad4. These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction.

Activin Receptors, Type I↗

PubMed1997

Characterization of the interactions between PDZ domains of the protein-tyrosine phosphatase PTPL1 and the carboxyl-terminal tail of Fas.

The intracellular protein-tyrosine phosphatase PTPL1 has five PDZ domains and one of them, PDZ 2, has previously been shown to interact with the C-terminal tail of Fas, a member of the tumor necrosis factor receptor family. Using a peptide binding assay, we show that not only PDZ 2 but also PDZ 4 of PTPL1 interacts with high affinity with peptides derived from the C terminus of Fas. The five most C-terminal amino acid residues of Fas influence the affinity of the interaction. Whereas the glutamine and isoleucine residues in the 4th and 5th positions from the C terminus affect the interaction in a negative and positive manner, respectively, the three C-terminal amino acid residues (SLV) are necessary and sufficient for a high affinity interaction to occur. Both the carboxyl group and side chain of the valine residue at the C terminus of Fas are essential, and the leucine and serine residues in the 2nd and 3rd positions, respectively, from the C terminus are important for the interactions with PDZ 2 and PDZ 4 of PTPL1.

Amino Acid Sequence↗

PubMed1997

Transforming growth factor (TGF-beta)-specific signaling by chimeric TGF-beta type II receptor with intracellular domain of activin type IIB receptor.

Members of the transforming growth factor-beta (TGF-beta) superfamily signal via different heteromeric complexes of two sequentially acting serine/threonine kinase receptors, i.e. type I and type II receptors. We generated two different chimeric TGF-beta superfamily receptors, i.e. TbetaR-I/BMPR-IB, containing the extracellular domain of TGF-beta type I receptor (TbetaR-I) and the intracellular domain of bone morphogenetic protein type IB receptor (BMPR-IB), and TbetaR-II/ActR-IIB, containing the extracellular domain of TGF-beta type II receptor (TbetaR-II) and the intracellular domain of activin type IIB receptor (ActR-IIB). In the presence of TGF-beta1, TbetaR-I/BMPR-IB and TbetaR-II/ActR-IIB formed heteromeric complexes with wild-type TbetaR-II and TbetaR-I, respectively, upon stable transfection in mink lung epithelial cell lines. We show that TbetaR-II/ActR-IIB restored the responsiveness upon transfection in mutant cell lines lacking functional TbetaR-II with respect to TGF-beta-mediated activation of a transcriptional signal, extracellular matrix formation, growth inhibition, and Smad phosphorylation. Moreover, TbetaR-I/BMPR-IB and TbetaR-II/ActR-IIB formed a functional complex in response to TGF-beta and induced phosphorylation of Smad1. However, complex formation is not enough for signal propagation, which is shown by the inability of TbetaR-I/BMPR-IB to restore responsiveness to TGF-beta in cell lines deficient in functional TbetaR-I. The fact that the TGF-beta1-induced complex between TbetaR-II/ActR-IIB and TbetaR-I stimulated endogenous Smad2 phosphorylation, a TGF-beta-like response, is in agreement with the current model for receptor activation in which the type I receptor determines signal specificity.

Activin Receptors↗

PubMed1997

Involvement of phosphatidylinositol 3'-kinase in stem-cell-factor-induced phospholipase D activation and arachidonic acid release.

We have shown previously that the stem cell factor (SCF) receptor undergoes phosphorylation on serine residues following ligand stimulation, and that this phopshorylation is dependent mainly on the activity of protein kinase C (PKC). In the present study, we have further investigated the molecular mechanisms behind SCF-stimulated activation of PKC, and found that SCF does not activate phosphatidylinositol-specific phospholipase C. In contrast, phospholipase D (PLD) is activated in response to SCF in a dose-dependent manner. Activation of PLD was not inhibited by calphostin C, an inhibitor of PKC. On the other hand, inhibitors of phosphatidylinositol PtdIns 3'-kinase (PtdIns 3'-kinase), i.e. wortmannin and LY294002, inhibited SCF-induced PLD activation. Moreover, a mutant SCF receptor in which Tyr721, which is responsible for activation of PtdIns 3'-kinase, is mutated to a phenylalanine residue was unable to mediate activation of PLD. Thus, PtdIns 3'-kinase appears to be essential for SCF-induced PLD activation. Furthermore, we demonstrate that phosphatidic acid (PtdH), generated through the action of PLD in response to SCF, is metabolized to diacylglycerol by dephosphorylation. Diacylglycerol can then activate PKC, and, moreover, after deacylation by a diacylglycerol lipase, yield arachidonic acid, an important second messenger in cell signaling.

Arachidonic Acid↗

PubMed1997

Involvement of phosphatidylinositide 3'-kinase and Rac in platelet-derived growth factor-induced actin reorganization and chemotaxis.

Previous work has suggested a role for phosphatidylinositide 3'-kinase (PI3-kinase) in platelet-derived growth factor (PDGF)-induced actin reorganization and chemotaxis. In support of this notion, we show in this report that the PI3-kinase inhibitor wortmannin inhibits chemotaxis of PDGF beta-receptor expressing porcine aortic endothelial (PAE/PDGFR-beta) cells. Treatment with wortmannin resulted in a dose-dependent decrease in chemotaxis with an IC50 value of about 15-20 nM. Higher concentrations of wortmannin also reduced basal random migration of transfected cells in the absence of PDGF. We also investigated the role of Rac in PDGF-induced actin reorganization and cell motility. Overexpression of wt Rac in PAE/PDGFR-beta cells led to an increased cell motility and edge ruffling in response to PDGF-BB, compared to control cells. In PAE/PDGFR-beta cells transfected with inducible V12Rac (a constitutively active Rac mutant), membrane ruffling occurred in the absence of PDGF stimulation and was independent of PI3-kinase activity. On the other hand, PAE/PDGFR-beta cells transfected with inducible N17Rac (a dominant negative Rac mutant) failed to show membrane ruffling in response to PDGF stimulation. Together with previous observations, these data indicate that activation of PI3-kinase is crucial for initiation of PDGF-induced cell motility responses and that Rac has a major role downstream of PI3-kinase, in this pathway.

Actins↗

PubMed1997

Association of coatomer proteins with the beta-receptor for platelet-derived growth factor.

The nonreceptor tyrosine kinase Src binds to and is activated by the beta-receptor for platelet-derived growth factor (PDGF). The interaction leads to Src phosphorylation of Tyr934 in the kinase domain of the receptor. In the course of the functional characterization of this phosphorylation, we noticed that components of 136 and 97 kDa bound to a peptide from this region of the receptor in a phosphorylation-independent manner. These components have now been purified and identified as alpha- and beta'-coatomer proteins (COPs), respectively. COPs are a family of proteins involved in the regulation of intracellular vesicle transport. In order to explore the functional significance of the interaction between alpha- and beta'-COP and the PDGF receptor, a receptor mutant was made in which the conserved histidine residue 928 was mutated to an alanine residue. The mutant receptor, which was unable to bind alpha- or beta'-COP, showed a normal ligand-induced autophosphorylation. The mutant receptor also behaved like the wildtype receptor with regard to biosynthesis and maturation, and mediated a mitogenic signal. The possible functional importance of the interaction between the PDGF beta-receptor and alpha- and beta'-COP, is discussed.

Amino Acid Sequence↗

PubMed1997

Simultaneous induction of stimulatory and inhibitory signals by PDGF.

Platelet-derived growth factor (PDGF) exerts its effects on cells via binding to structurally similar alpha- and beta-tyrosine kinase receptors. Ligand binding induces receptor dimerization and autophosphorylation which allows docking of SH2 domain containing signal transduction molecules. At least 10 different SH2 domain molecules bind in a specific manner to 11 identified autophosphorylated tyrosine residues in the PDGF beta-receptor, thereby initiating signaling pathways leading to cell growth and motility. Available information indicates that there is considerable cross-talk between different signaling pathways, and that stimulatory and inhibitory signals often are initiated in parallel.

Cell Division↗

PubMed1997

Phosphorylation of a 72-kDa protein in PDGF-stimulated cells which forms complex with c-Crk, c-Fyn and Eps15.

Ligand-induced activation of the beta-receptor for platelet-derived growth factor (PDGF) induces tyrosine phosphorylation of a number of downstream signaling proteins. In the present study, we used two-dimensional gel electrophoresis to characterize the spectrum of proteins phosphorylated in response to PDGF stimulation in porcine aortic endothelial cells expressing PDGF beta-receptors. Several previously known substrates for the PDGF beta-receptor were identified as well as a novel substrate of 72 kDa. The 72-kDa component could be co-immunoprecipitated in complex with the adaptor protein c-Crk, the non-receptor tyrosine kinase c-Fyn and the signaling molecule Eps15. The results obtained suggests that the 72-kDa protein might play an important role in signaling via the PDGF beta-receptor, coupling non-receptor tyrosine kinases of the Src family with c-Crk and Eps15.

Animals↗

PubMed1997

Latent transforming growth factor-beta complex in Chinese hamster ovary cells contains the multifunctional cysteine-rich fibroblast growth factor receptor, also termed E-selectin-ligand or MG-160.

Transforming growth factor-beta (TGF-beta) is secreted as latent high molecular mass complexes from producer cells. The N-terminal precursor remnant, also called latency-associated peptide (LAP), forms a non-covalently linked complex with TGF-beta and confers the latency to TGF-beta. In human platelets and certain other cell types, latent TGF-beta binding protein-1 (LTBP-1) is disulphide-linked to LAP, and forms complexes of more than 230 kDa. In addition, LTBP-2 and -3, which are structurally similar to LTBP-1, can be part of latent TGF-beta complexes. In Chinese hamster ovary (CHO) cells transfected with the TGF-beta1 cDNA, a major part of the latent TGF-beta secreted into the medium is a 100-kDa small latent complex containing TGF-beta and LAP. In addition, we found two other forms of latent TGF-beta complexes, i.e. a 220-kDa complex containing LTBP-1, and a 220-kDa complex containing a 140-kDa protein. Purification of the 140-kDa component, termed latent TGF-beta complexed protein-1 (LTCP-1), followed by amino acid sequencing and cDNA cloning from a CHO cell cDNA library, revealed that it is a hamster counterpart of a previously identified, multifunctional protein known as chicken cysteine-rich fibroblast growth factor (FGF) receptor, mouse E-selectin-ligand and rat MG-160 (a 160-kDa membrane sialoglycoprotein of the Golgi apparatus). Immunoprecipitation of LTCP-1 and TGF-beta1 from CHO cells stably transfected with TGF-beta1 precursor cDNA revealed that the expressed protein forms a complex with LAP, and that a major part of the complex is secreted. Northern blot analysis showed that mRNA for LTCP-1 was expressed in large amounts in testis, ovary and placenta, but less abundantly in other tissues. These results suggest that TGF-beta, produced in certain cell types, may form a complex with LTCP-1, which may have different properties compared with other latent TGF-beta complexes. It remains to be investigated whether the complex formation between LTCP-1 and TGF-beta1 also occurs in other cells, whether the association between them occurs in the Golgi complex, and whether it affects the interaction of LTCP-1 with FGF or E-selectin.

Adult↗

PubMed1997

Phosphorylation site-specific inhibition of platelet-derived growth factor beta-receptor autophosphorylation by the receptor blocking tyrphostin AG1296.

The mechanism of action of AG1296, a potent and specific inhibitor of the platelet-derived growth factor (PDGF) receptor tyrosine kinase [Kovalenko, M., Gazit, A., Böhmer, A., Rorsman, Ch., Rönnstrand, L., Heldin, C.-H., Waltenberger, J., Böhmer, F. D., & Levitzki, A. (1994) Cancer Res. 54, 6106-6114] was investigated. This quinoxalin-type tyrphostin neither interferes with PDGF-BB binding to the PDGF beta-receptor nor has any effect on receptor dimerization. Kinetic analysis of the inhibition was carried out using a synthetic peptide substrate (KY751) corresponding to the sequence around tyrosine 751 autophosphorylation site of the PDGF receptor. It revealed purely competitive inhibition vis-à-vis ATP, mixed competitive inhibition vis-a-vis the peptide substrate for the non-activated receptor, and mixed competitive inhibition vis-à-vis both substrates for the activated receptor. Thus, the type of inhibition apparently changes upon receptor activation, indicating conformational changes at the ATP-binding site. The high degree of selectivity for the tyrphostin AG1296 might result from the complex type of interaction with the active center of the receptor as revealed by the kinetic analysis. Dose-response curves for inhibition of the phosphorylation of individual autophosphorylation sites of the PDGF beta-receptor by AG1296 were different, phosphorylation of tyrosine 857 being the most susceptible to inhibition. Thus, phosphorylation of tyrosine 857 in the PDGF receptor kinase domain seems dispensable for partial kinase activation. The findings are discussed in relation to current models of receptor tyrosine kinase activation.

Adenosine Triphosphate↗

PubMed1997

Immunoglobulin-like domain 4-mediated receptor-receptor interactions contribute to platelet-derived growth factor-induced receptor dimerization.

Platelet-derived growth factor (PDGF) is a dimeric growth factor that activates its tyrosine kinase receptor by inducing receptor dimerization. In this study, we investigated if receptor-receptor interactions, in addition to ligand-receptor interactions, contribute to the ligand-induced dimerization of the PDGF receptors. Analysis of two deletion mutants of the PDGF alpha-receptor indicated a role for Ig-like domain 4 in ligand-receptor or receptor-receptor interactions. When the fourth Ig-like domain of the PDGF alpha-receptor instead was replaced with the corresponding sequence of the stem cell factor receptor, the binding of PDGF-AA and -BB was not affected, nor was the ability to form homodimeric receptor complexes. This indicates that Ig-like domain 4 does not participate in ligand-receptor interactions. However, the chimeras did not form heterodimers with wild-type PDGF alpha- or beta-receptors. Together, these findings suggest that Ig-like domain 4 mediates specific receptor-receptor interactions. This notion was also supported by the finding that a soluble form of Ig-like domain 4 of the PDGF alpha-receptor acted as a PDGF alpha-receptor antagonist. We conclude that specific receptor-receptor interactions contribute to PDGF receptor dimerization in vivo and that complementary epitopes in Ig-like domain 4 mediate these interactions. Our experiments also identify Ig-like domain 4 as a target for PDGF antagonists.

Animals↗

PubMed1997

Identification of Smad2, a human Mad-related protein in the transforming growth factor beta signaling pathway.

Transforming growth factor-beta (TGF-beta) superfamily members are multifunctional cytokines that exert their effects via heteromeric complexes of two distinct serine and threonine kinase receptors. Drosophila mothers against decapentaplegic and related genes in Caenorhabditis elegans, Xenopus, and mammals were shown to function downstream in the intracellular signaling pathways of TGF-beta superfamily members. Here we report the cloning of a Mad-related protein, termed Sma- and Mad-related protein 2 (Smad2). TGF-beta stimulated the phosphorylation and nuclear translocation of Smad2 in nontransfected Mv1Lu cells. In addition, we demonstrated that TGF-beta and activin mediated phosphorylation of Smad2 after its overexpression with appropriate type I and II receptors in COS cells. Smad2 and Smad1 were found to be broadly expressed in human tissues. Smad2 is closely linked to DPC4 on chromosome 18q21.1, a region often deleted in human cancers. Cells that lack Smad2 may escape from TGF-beta-mediated growth inhibition and promote cancer progression.

Animals↗

PubMed1997

Characterization of a 60-kDa cell surface-associated transforming growth factor-beta binding protein that can interfere with transforming growth factor-beta receptor binding.

We have characterized a 60-kDa transforming growth factor-beta (TGF-beta) binding protein that was originally identified on LNCaP adenocarcinoma prostate cells by affinity cross-linking of cell surface proteins by using 125I-TGF-beta 1. Binding of 125I-TGF-beta 1 to the 60-kDa protein was competed by an excess of unlabeled TGF-beta 1 but not by TGF-beta 2, TGF-beta 3, activin, or osteogenic protein-1 (OP-1), also termed bone morphogenetic protein-7 (BMP-7). In addition, no binding of 125I-TGF-beta 2 and 125I-TGF-beta 3 to the 60-kDa binding protein on LNCaP cells could be demonstrated by using affinity labeling techniques. The 60-kDa TGF-beta binding protein showed no immunoreactivity with antibodies against the known type I and type II receptors for members of the TGF-beta superfamily. Treatment of LNCaP cells with 0.25 M NaCl, 1 microgram/ml heparin, or 10% glycerol caused a release of the 60-kDa protein from the cell surface. In addition, we found that the previously described TGF-beta type IV receptor on GH3 cells, which does not form a heterometric complex with TGF-beta receptors, could be released from the cell surface by these same treatments. This suggests that the 60-kDa protein and the similarly sized TGF-beta type IV receptor are related proteins. The eluted 60-kDa LNCaP protein was shown to interfere with the binding of TGF-beta to the TGF-beta receptors. Thus, the cell surface-associated 60-kDa TGF-beta binding protein may play a role in regulating TGF-beta binding to TGF-beta receptors.

Adaptor Proteins, Signal Transducing↗

PubMed1997

[Functions of the transforming growth factor-beta superfamily in eyes].

One human body is composed of 6 x 10(13) cells, and eyes are also composed of many cells of different functions. The cellular functions and intercellular interaction are regulated by many regulators including cytokines and growth factors to maintain the homeostasis. The transforming growth factor-beta (TGF-beta) superfamily, a large family of multifunctional factors, regulates various cellular functions, including cellular proliferation, migration, differentiation, apoptosis and extracellular matrix production. The TGF-beta superfamily contains about 30 multifunctional factors, and is divided into several families according to the sequence homology. The TGF-beta family, the activin family, and bone morphogenic proteins belong to the TGF-beta superfamily. TGF-beta superfamily members transduce signals through type I and type II serine/threonine type transmembrane receptors. The signals are transduced from receptors through nuclei by Smad family members, which are phosphorylated by the activated type I receptors and translocate from cytoplasm into nuclei. TGF-beta family members and the TGF-beta superfamily receptor family are expressed in ocular tissues including the cornea, ciliary epithelium, lens epithelium, retina, and blood vessels. This observation suggests the importance of the TGF-beta superfamily in eyes. Smad family members (Smad 1, Smad 2, Smad 3 and Smad 4) are expressed in the cultured retinal pigmant epithelial cell line (D407), in which TGF-beta and activin A stimulate the translocation of Smad 2, but not Smad 1 into nuclei, whereas bone morphogenetic protein (BMP) stimulates that of Smad 1, but not Smad 2. TGF-beta superfamily members play important roles in the pathogenesis of retinal neovascularization and in the wound healing process of corneal tissue. TGF-beta inhibits the endothelial functions, but, stimulates angiogenesis in vivo. TGF-beta is involved in the formation of abnormal connective tissue in corneal wound healing. In these processes, many cytokines and growth factors are involved, interacting with each other and forming networks. It is mandatory to clarify the networks to investigate molecular pathogenesis and new therapeutic agents.

Diabetic Retinopathy↗

PubMed1996

Grb7 is a downstream signaling component of platelet-derived growth factor alpha- and beta-receptors.

Ligand stimulation of the platelet-derived growth factor (PDGF) alpha- or beta-receptors leads to activation of their intrinsic tyrosine kinases and autophosphorylation of tyrosine residues. Grb7 is an SH2 and PH domain-containing molecule that is known to be overexpressed in some breast cancer tissues and cell lines. Here we show that the SH2 domain of Grb7 can directly bind to the autophosphorylated PDGF beta-receptor in vitro. Grb7 association to the PDGF beta-receptor was dramatically reduced by replacement of tyrosine residues 716 or 775 with phenylalanine residues. Synthetic phosphorylated peptides containing Tyr-716 or Tyr-775 inhibited binding of the Grb7 SH2 domain to the autophosphorylated PDGF beta-receptor in a manner similar to but distinct from the binding of the Grb2 SH2 domain. Grb7 associated with activated PDGF beta-receptors in vivo, and the association was dramatically reduced by substitution of Tyr-716 or Tyr-775 with a phenylalanine residue. Furthermore, complex formation between Shc and Grb7 was observed after ligand stimulation of PDGF alpha- or beta-receptors in cells transfected with Grb7 cDNA or in the breast cancer cell line BT-474. Thus, Grb7 is implicated in PDGF signaling pathways in certain cell types by binding to the receptor directly or indirectly via Shc.

Adaptor Proteins, Signal Transducing↗

PubMed1996

Phosphorylation of Ser165 in TGF-beta type I receptor modulates TGF-beta1-induced cellular responses.

Transforming growth factor-beta (TGF-beta) signals via an oligomeric complex of two serine/threonine kinase receptors denoted TGF-beta type I receptor (TbetaR-I) and type II receptor (TbetaR-II). We investigated the in vivo phosphorylation sites in TbetaR-I and TbetaR-II after complex formation. Phosphorylation of TbetaR-II was observed at residues in the C-terminus (Ser549 and Ser551) and at residues in the juxtamembrane domain (Ser223, Ser226 and Ser227). TGF-beta1 induced in vivo phosphorylation of serine and threonine residues in the juxtamembrane domain of TbetaR-I in a region rich in glycine, serine and threonine residues (GS domain; Thr185, Thr186, Ser187, Ser189 and Ser191), and more N-terminal of this region (Ser165). Phosphorylation in the GS domain has been shown previously to be involved in activation of the TbetaR-I kinase. We show here that phosphorylation of TbetaR-I at Ser165 is involved in modulation of TGF-beta1 signaling. Mutations of Ser165 in TbetaR-I led to an increase in TGF-beta1-mediated growth inhibition and extracellular matrix formation, but, in contrast, to decreased TGF-beta1-induced apoptosis. A transcriptional activation signal was not affected. Mutations of Ser165 changed the phosphorylation pattern of TbetaR-I. These observations suggest that TGF-beta receptor signaling specificity is modulated by phosphorylation of Ser165 of TbetaR-I.

Amino Acid Sequence↗