Biomedical subjects

A Ullrich

Publications and source records attributed to A Ullrich.

At least 73 records · Page 4Linked to original sources

PubMed1999

Epidermal growth factor receptors: critical mediators of multiple receptor pathways.

Recently, the receptor for epidermal growth factor (EGF) was identified as a downstream element in different signaling pathways. This expanded its classical function as a receptor for EGF-like ligands to a role as mediator of diverse signaling systems and as a switch point of a cellular communication network. In addition, several downstream targets, (e.g. Smad proteins and STATs) into which signals from synergistic and antagonistic signaling pathways converge, were identified.

Animals↗

PubMed1999

Inhibition of tumor growth, angiogenesis, and microcirculation by the novel Flk-1 inhibitor SU5416 as assessed by intravital multi-fluorescence videomicroscopy.

Vascular endothelial growth factor (VEGF) plays a fundamental role in mediating tumor angiogenesis and tumor growth. Here we investigate the direct effect of a novel small molecule inhibitor of the Flk-1-mediated signal transduction pathway of VEGF, SU5416, on tumor angiogenesis and microhemodynamics of an experimental glioblastoma by using intravital multifluorescence videomicroscopy. SU5416 treatment significantly suppressed tumor growth. In parallel, SU5416 demonstrated a potent antiangiogenic activity, resulting in a significant reduction of both the total and functional vascular density of the tumor microvasculature, which indicates an impaired vascularization as well as significant perfusion failure in treated tumors. This malperfusion was not compensated for by changes in vessel diameter or recruitment of nonperfused vessels. Analyses of the tumor microcirculation revealed significant microhemodynamic changes after angiogenesis blockage such as a higher red blood cell velocity and blood flow in remnant tumor vessels when compared with controls. Our results demonstrate that the novel antiangiogenic concept of targeting the tyrosine kinase of Flk-1/KDR by means of a small molecule inhibitor represents an efficient strategy to control growth and progression of angiogenesis-dependent tumors. This study provides insight into microvascular consequences of Flk-1/KDR targeting in vivo and may have important implications for the future treatment of angiogenesis-dependent neoplasms.

Animals↗

PubMed1998

The cellular localization of the murine serine/arginine-rich protein kinase CLK2 is regulated by serine 141 autophosphorylation.

Pre-mRNA splicing is catalyzed by a multitude of proteins including serine/arginine-rich (SR) proteins, which are thought to play a crucial role in the formation of spliceosomes and in the regulation of alternative splicing. SR proteins are highly phosphorylated, and their kinases are believed to regulate the recruitment of SR proteins from nuclear storage compartments known as speckles. Recently, a family of autophosphorylating kinases termed CLK (CDC2/CDC28-like kinases) was shown to phosphorylate SR proteins and to influence alternative splicing in overexpression systems. Here we used endogenous CLK2 protein to demonstrate that it displays different biochemical characteristics compared with its overexpressed protein and that it is differentially phosphorylated in vivo. Furthermore, CLK2 changed its nuclear localization upon treatment with the kinase inhibitor 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole. We have also identified a CLK2 autophosphorylation site, which is highly conserved among all CLK proteins, and we show by site-directed mutagenesis that its phosphorylation influences the subnuclear localization of CLK2. Our data suggest that CLK2 localization and possibly activity are influenced by a balance of CLK2 autophosphorylation and the regulation by CLK2 kinases and phosphatases.

Alternative Splicing↗

PubMed1998

PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif.

Protein kinases and phosphatases regulate the activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2) by controlling the phosphorylation of specific residues. We report the physical and functional association of ERK1/2 with the PTP-SL and STEP protein tyrosine phosphatases (PTPs). Upon binding, the N-terminal domains of PTP-SL and STEP were phosphorylated by ERK1/2, whereas these PTPs dephosphorylated the regulatory phosphotyrosine residues of ERK1/2 and inactivated them. A sequence of 16 amino acids in PTP-SL was identified as being critical for ERK1/2 binding and termed kinase interaction motif (KIM) (residues 224-239); it was shown to be required for phosphorylation of PTP-SL by ERK1/2 at Thr253. Co-expression of ERK2 with catalytically active PTP-SL in COS-7 cells impaired the EGF-induced activation of ERK2, whereas a PTP-SL mutant, lacking PTP activity, increased the ERK2 response to EGF. This effect was dependent on the presence of the KIM on PTP-SL. Furthermore, ERK1/2 activity was downregulated in 3T3 cells stably expressing PTP-SL. Our findings demonstrate the existence of a conserved ERK1/2 interaction motif within the cytosolic non-catalytic domains of PTP-SL and STEP, which is required for the regulation of ERK1/2 activity and for phosphorylation of the PTPs by these kinases. Our findings suggest that PTP-SL and STEP act as physiological regulators of the ERK1/2 signaling pathway.

3T3 Cells↗

PubMed1998

Characterization of KIF1C, a new kinesin-like protein involved in vesicle transport from the Golgi apparatus to the endoplasmic reticulum.

Kinesins comprise a large family of microtubule-based motor proteins, of which individual members mediate specific types of motile processes. Using the ezrin domain of the protein-tyrosine phosphatase PTPD1 as a bait in a yeast two-hybrid screen, we identified a new kinesin-like protein, KIF1C. KIF1C represents a member of the Unc104 subfamily of kinesin-like proteins that are involved in the transport of mitochondria or synaptic vesicles in axons. Like its homologues, the 1103-amino acid protein KIF1C consists of an amino-terminal motor domain followed by a U104 domain and probably binds to target membranes through carboxyl-terminal sequences. Interestingly, KIF1C was tyrosine-phosphorylated after peroxovanadate stimulation when overexpressed in 293 or NIH3T3 fibroblasts or in native C2C12 cells. Using immunofluorescence, we found that KIF1C is localized primarily at the Golgi apparatus. In brefeldin A-treated cells, the Golgi membranes and KIF1C redistributed to the endoplasmic reticulum (ER). This brefeldin A-induced flow of Golgi membranes into the ER was inhibited in cells transiently overexpressing catalytically inactive KIF1C. In conclusion, our data suggest an involvement of tyrosine phosphorylation in the regulation of the Golgi to ER membrane flow and describe a new kinesin-like motor protein responsible for this transport.

Amino Acid Sequence↗

PubMed1998

SAF-B protein couples transcription and pre-mRNA splicing to SAR/MAR elements.

Interphase chromatin is arranged into topologically separated domains comprising gene expression and replication units through genomic sequence elements, so-called MAR or SAR regions (for matrix- or scaffold-associating regions). S/MAR regions are located near the boundaries of actively transcribed genes and were shown to influence their activity. We show that scaffold attachment factor B (SAF-B), which specifically binds to S/MAR regions, interacts with RNA polymerase II (RNA pol II) and a subset of serine-/arginine-rich RNA processing factors (SR proteins). SAF-B localized to the nucleus in a speckled pattern that coincided with the distribution of the SR protein SC35. Furthermore, we show that overexpressed SAF-B induced an increase of the 10S splice product using an E1A reporter gene and repressed the activity of an S/MAR flanked CAT reporter gene construct in vivo . This indicates an association of SAF-B with SR proteins and components of the transcription machinery. Our results describe the coupling of a chromatin organizing S/MAR element with transcription and pre-mRNA processing components and we propose that SAF-B serves as a molecular base to assemble a 'transcriptosome complex' in the vicinity of actively transcribed genes.

3T3 Cells↗

PubMed1998

Ligand-independent activation of platelet-derived growth factor receptor is a necessary intermediate in lysophosphatidic, acid-stimulated mitogenic activity in L cells.

Growth factor-derived mitogenic signals from the cell surface are transmitted to the nucleus via receptor tyrosine kinases (RTKs), the adaptor proteins Shc and Grb2, and a Ras-dependent protein kinase cascade that activates the extracellular signal regulated kinase (ERK) subfamily of mitogen-activated protein kinases. ERKs also are activated by hormones that stimulate G protein-coupled receptors (GPCRs). We report here that, in agreement with previous data, the epidermal growth factor receptor (EGFR) is a signaling intermediate in ERK activation by GPCRs. Of import, we show that cross-talk between two classes of surface receptors, RTKs and GPCRs, is a general feature. Lysophosphatidic acid not only induces ligand-independent tyrosine autophosphorylation of EGFR but also of platelet-derived growth factor beta receptor (PDGF-beta-R) as shown by detection of tyrosine phosphorylation and by the use of specific inhibitors of RTKs. The cross-talk appears to be cell type-specific: In L cells that lack EGFR, lysophosphatidic acid-induced Shc and ERK activation is prevented completely by specific inhibition of PDGFR, whereas in COS-7 cells expressing only EGFR, the pathway via EGFR is chosen. In Rat-1 cells, however, that express both EGFR and PDGFR, the EGFR pathway dominates.

Animals↗

PubMed1998

Growth hormone regulation of SIRP and SHP-2 tyrosyl phosphorylation and association.

SIRPs (signal-regulatory proteins) are a family of transmembrane glycoproteins that were identified by their association with the Src homology 2 domain-containing protein-tyrosine phosphatase SHP-2 in response to insulin. Here we examine whether SIRPalpha and SHP-2 are signaling molecules for the receptors for growth hormone (GH), leukemia inhibitory factor (LIF), or interferon-gamma (IFNgamma), cytokine receptor superfamily members that bind to and activate Janus kinase 2 (JAK2). In 3T3-F442A fibroblasts, GH rapidly stimulates tyrosyl phosphorylation of both SIRPalpha and SHP-2 and enhances association of SHP-2 with SIRPalpha. Consistent with JAK2 binding and phosphorylating SIRPalpha in response to GH, co-expression of SIRPalpha and JAK2 in COS cells results in tyrosyl phosphorylation of SIRPalpha and JAK2 association with SIRPalpha. LIF does not stimulate tyrosyl phosphorylation of SIRPalpha but stimulates greater tyrosyl phosphorylation of SHP-2 than GH. Additionally, LIF enhances association of SHP-2 with the gp130 subunit of the LIF receptor signaling complex. IFNgamma, which stimulates JAK2 to a greater extent than LIF, is ineffective at stimulating tyrosyl phosphorylation of SIRPalpha or SHP-2. These results suggest that SIRPalpha is a signaling molecule for GH but not for LIF or IFNgamma. Differential phosphorylation of SIRPalpha and SHP-2 may contribute to the distinct physiological effects of these ligands.

3T3 Cells↗

PubMed1998

The "VH1-like" dual-specificity protein tyrosine phosphatases.

The number of dual-specificity protein tyrosine phosphatases has grown considerably in the last few years, and thus it would be helpful to organize these novel enzymes. The simple term "VH1-like" or "dual-specificity" phosphatase does not adequately reflect the different subclasses within this new and important phosphatase subfamily. In this article, we review the salient features of dual-specificity phosphatases and propose a novel classification scheme of these enzymes based on their structural motifs. Classification of dual-specificity phosphatases based on their motifs should serve as a useful organizational framework for bringing together this now large subgroup of phosphatases. Moreover, this classification scheme may hold predictive value, since some of these motifs may hold the key to new, undiscovered functional properties.

Amino Acid Sequence↗

PubMed1998

90K (MAC-2 BP) gene expression in breast cancer and evidence for the production of 90K by peripheral-blood mononuclear cells.

The tumor-derived antigen 90K (Mac-2 BP) is a widely expressed, secreted glycoprotein found in the serum of healthy individuals and at elevated levels in the serum of patients with breast cancer and other types of cancer. The precise function of 90K, particularly in the context of tumor-host relationships, has not yet been established. In this study, the clinical significance of 90K mRNA expression was studied in relation to other established prognostic parameters in 86 patients with primary breast carcinoma. The 2.2-kb 90K message was detected in all tumor samples, but there was marked variation in expression levels from tumor to tumor. Patients were classified into 2 groups on the basis of 90K expression: group 1 (n = 62) included patients with low expression, and group 2 (n = 24) consisted of patients with high expression. An inverse significant correlation was found between the levels of 90K mRNA expression and overexpression of c-erbB2/Neu receptor kinase, a marker of poor prognosis for patients with breast cancer. There was no significant difference between the groups with respect to tumor size, number of involved axillary lymph nodes, hormone-receptor status, p53 expression or proliferation activity as estimated by Ki-67 count. Similarly, no association was found between the level of 90K expression and the risk of death from breast cancer. These data are at variance with published findings showing that high serum 90K levels are associated with poor survival. Significantly, investigation of 90K-gene expression in peripheral-blood mononuclear cells (PBMC) revealed higher levels of 90K message in PBMC of breast-cancer patients than in healthy individuals. This new finding suggests that PBMC activated in response to tumor growth and progression may be an important source of serum 90K in breast cancer.

Adult↗

PubMed1998

Mutant forms of the protein tyrosine phosphatase alpha show differential activities towards intracellular substrates.

BHK cells overexpressing five million IR (BHK-IR) respond to insulin with reduced growth and detachment from the dish surface. We have recently identified protein tyrosine phosphatase (PTP) alpha as a negative regulator of the insulin receptor (IR) tyrosine kinase that is able to rescue BHK-IR cells from the insulin effect. In this report we describe the effect of several point mutations in PTP alpha on the phosphatase activity and regulation of insulin signaling in BHK-IR cells. Analysis of total cellular phosphotyrosine protein revealed several molecules that were dephosphorylated when PTP alpha or a phosphatase active mutant was overexpressed. By contrast, some proteins were tyrosine phosphorylated as strong or to an even higher extent as in the parental line when PTP alpha Y798F was present. We conclude that mutation of the carboxyterminal tyrosine in PTP alpha uncovers a dual function of this phosphatase in BHK cells: reduction of the IR signal and activation of an endogenous kinase.

Animals↗

PubMed1998

Protein kinase C isoforms alpha, delta and theta require insulin receptor substrate-1 to inhibit the tyrosine kinase activity of the insulin receptor in human kidney embryonic cells (HEK 293 cells).

Protein kinase C (PKC) isoforms are potentially important as modulators of the insulin signalling chain and could be involved in the pathogenesis of cellular insulin resistance. We have previously shown that phorbol ester stimulated PKC beta1 and beta2 as well as tumor necrosis factor-alpha (TNFalpha) stimulated PKC epsilon inhibit human insulin receptor (HIR) signalling. There is increasing evidence that the insulin receptor substrate-1 (IRS-1) is involved in inhibitory signals in insulin receptor function. The aim of the present study was to elucidate the role of IRS-1 in the inhibitory effects of protein kinase C on human insulin receptor function. HIR, PKC isoforms (alpha, beta1, beta2, gamma, delta, epsilon, eta, theta and zeta) and IRS-1 were coexpressed in human embryonic kidney (HEK) 293 cells. PKCs were activated by preincubation with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (CTPA) (10(-7) mol/l) following insulin stimulation. While PKCs alpha, delta and theta were not inhibitory in HEK 293 cells which were transfected only with HIR and PKC, additional transfection of IRS-1 induced a strong inhibitory effect of these PKC isoforms being maximal for PKC theta (99 +/- 1.8% inhibition of insulin stimulated receptor autophosphorylation, n = 7, p < 0.001). No effect was seen with PKC gamma, epsilon, zeta and eta while the earlier observed insulin receptor kinase inhibition of PKC beta2 was further augmented (91 +/- 13%, n = 7, p < 0.001 instead of 45% without IRS-1). The strong inhibitory effect of PKC theta is accompanied by a molecular weight shift of IRS-1 (183 kDa vs 180 kDa) in the sodium dodecyl sulphate polyacrylamide gel. This can be reversed by alkaline phosphatase treatment of IRS-1 suggesting that this molecular weight shift is due to an increased phosphorylation of IRS-1 on serine or threonine residues. In summary, these data show that IRS-1 is involved in the inhibitory effect of the PKC isoforms alpha, beta2, delta and theta and it is likely that this involves serine/threonine phosphorylation of IRS-1.

Alkaline Phosphatase↗

PubMed1998

The suitability and application of a GFP-actin fusion protein for long-term imaging of the organization and dynamics of the cytoskeleton in mammalian cells.

The product of a GFP-actin gene fusion, permanently or transiently transfected in diverse mammalian cell lines, was shown to be a suitable, intrinsic probe of both the organization and dynamics of the actin cytoskeleton. In live Swiss 3T3 and NIH 3T3 cells, the fusion protein was found to accumulate in lamellipodia, filopodia, focal contacts and stress fibers. Furthermore, comparisons of fluorescence images of GFP-actin and Cy3.5-phalloidin, an independent marker of F-actin, in permeabilized cells showed a complete overlap of the two fluorescence signals. In GFP-actin-transfected Hela cells that had been infected with Listeria monocytogenes, the fluorescence of the fusion protein was shown to dynamically associate in the F-actin rich comet tail that formed behind a motile bacterium. In stable transfectants of PC12 cells, GFP-actin constituted on the average 5% of the total actin - these cells exhibited normal growth behavior and responded to treatment with nerve growth factor by extending neurite-like extensions, the filopodia-like tips of which were densely packed with filamentous GFP-actin. Finally, the photobleaching decay time of GFP-actin in live cells of 63 seconds was much longer than that of fluorescein-labeled actin conjugates and little or no damage to the cytoskeleton was found during the photobleaching of GFP-actin. Having shown the suitability of GFP-actin as a probe of the cytoskeleton, its fluorescence was used in long-term imaging studies aimed at documenting changes in the cytoskeleton of rat bladder NBT-II carcinoma cells during the 24-hour growth factor-mediated epithelia to mesenchyme transformation. The intrinsic fluorescent probe was also used to investigate the organization of the actin cytoskeleton and behavior of individual mesenchyme NBT-II cells slowly migrating through a colony of epithelia cells.

3T3 Cells↗

PubMed1998

Differential expression of MAM-subfamily protein tyrosine phosphatases during mouse development.

The MAM-subfamily of type II transmembrane protein tyrosine phosphatases (PTPases) currently comprises the enzymes PTPkappa, PTPmu and PCP2. In an effort to elucidate the individual physiological roles of these closely related proteins we performed a detailed analysis of their mRNA transcript distributions at different stages of mouse embryogenesis and postnatal brain development. Our in situ hybridization studies revealed distinct and complementary expression patterns of PTPkappa, PTPmu and PCP2 transcripts. Based on our results and previous reports we discuss MAM-PTPases as a new class of morphoregulatory molecules.

Amino Acid Sequence↗

PubMed1998

SHP-2, SH2-containing protein tyrosine phosphatase-2.

SHP-2 is an ubiquitously expressed cytosolic protein tyrosine phosphatase composed of two amino-terminal SH2 domains, a central phosphatase domain and a carboxy-terminal tail. Upon activation of cells with different stimuli, SHP-2 is recruited to the plasma membrane where it can associate with a number of tyrosine phosphorylated molecules, including receptor tyrosine kinases (e.g. growth factor receptors), multisite adapter proteins and cell adhesion molecules. SHP-2 is thought to function as a positive mediator of signals generated by activated membrane receptor complexes although the number and diversity of binding partners and substrates identified thus far suggests that it may have other functions. It is likely that several negative regulatory influences exist but that these are obscured by its positive function making the investigation of the inhibitory effects of this phosphatase difficult. The positive regulatory role of SHP-2 in signal cascades leading to cell growth suggests involvement in tumorigenesis, raising the possibility that SHP-2 may be a target in the treatment of some forms of cancer.

Alternative Splicing↗

PubMed1998

Differential effect on TCR:CD3 stimulation of a 90-kD glycoprotein (gp90/Mac-2BP), a member of the scavenger receptor cysteine-rich domain protein family.

We studied the effects of a 90-kD glycoprotein (gp90/Mac-2BP) belonging to the scavenger receptor family, present in normal serum and at increased levels in inflammatory disease and cancer patients, on some T cell function parameters. Whereas the lymphocyte proliferative response to non-specific mitogens such as phytohaemagglutinin (PHA) and concanavalin A (Con A), but not pokeweed mitogen (PWM), was strongly reduced, probably due to the lectin-binding properties of gp90/Mac-2BP, the response to T cell receptor (TCR) agonists such as superantigens and allogeneic cells was potentiated. When lymphocytes were stimulated with different anti-TCR:CD3 MoAbs, both in soluble and solid-phase form, gp90/Mac-2BP was able to down-regulate the proliferative response to anti-CD3 MoAb, whereas the response to anti-TCR alphabeta MoAb was enhanced. A similar differential effect was observed when a MoAb against CD5 (another member of the scavenger receptor superfamily) was added to anti-CD3 or anti-TCR-stimulated cells; anti-CD5 MoAb strongly down-modulated the CD3-mediated response, whereas its presence in culture was associated with potentiation of the response to TCR alphabeta agonists. gp90/Mac-2BP was able per se to up-regulate Ca2+ levels in freshly isolated lymphocytes; moreover, its presence in culture was associated with increased Ca2+ mobilization following stimulation with anti-TCR alphabeta, but not anti-CD3 MoAb. These data indicate that gp90/Mac-2BP could be able to influence some immune responses, possibly through multiple homologous interactions with other members of the scavenger receptor family; moreover, our findings suggest that signalling through the different components of the TCR:CD3 complex may follow distinct activation pathways into the cells.

3T3 Cells↗

PubMed1998

Characterization of angiogenesis and microcirculation of high-grade glioma: an intravital multifluorescence microscopic approach in the athymic nude mouse.

The current study follows angiogenesis and microcirculatory changes associated with malignant glioma growth by means of an intravital fluorescence microscopic approach, which allows for the direct and continuous visualization of the glioma microvasculature and its quantitative analysis. Fluorescently labeled C6 rat glioma cells (5 x 10(5)) were implanted into dorsal skinfold chamber preparations of athymic nude mice. Glioma growth, vascularization, microhemodynamics, vascular permeability, and leukocyte-endothelial cell interactions were simultaneously followed over a 22-day observation period using intravital epiillumination microscopy and a multifluorescent labeling technique. Analysis of the process of glioma vascularization revealed three stages with distinct microvascular characteristics: avascular stage (days 0 to 6), lag of glioma growth but initial glioma-induced angiogenesis within the host tissue in peritumoral areas; early vascular stage (days 6 to 14), glioma cell proliferation associated with a spatially homogeneous development of a glioma microvasculature; and late vascular stage (days 14 to 22), exponential tumor growth and expansion (> 400 mm3) with high vascular densities in the peritumoral region and reduced vascularization (microvascular perfusion) in the glioma center. Within the center, the functional vessel length per area correlated inversely with glioma size (P < 0.01). In the peritumoral region, functional vessel length per area was independent of glioma size, indicating persistent, high angiogenic activity throughout the observation period. Thus, the microvasculature of mature gliomas revealed a microvascular zonal division with a progressive reduction of the functional vessel length per area within the tumor center. The perfusion failure of individual microvessels within the glioma center was partly compensated by an increase of diameters (P < 0.05), and thus by an increase of blood flow in these functional microvessels (P < 0.05) over time. Histologic analysis demonstrated both expanding and infiltrating growth patterns, as well as focal necroses on day 22. These are the first data from repeated in vivo analysis of glioma growth, vascularization, and microcirculation.

Animals↗

PubMed1998

Activation of phosphatidylinositol 3-kinase is necessary for differentiation of FDC-P1 cells following stimulation of type III receptor tyrosine kinases.

Signaling molecules that are responsible for proliferation and differentiation of hematopoietic cells following ectopic expression of receptor tyrosine kinases (RTKs) were investigated in the interleukin 3 (IL-3)-dependent hematopoietic cell line, FDC-P1. Cells were transfected with human platelet-derived growth factor receptor (PDGF-R), macrophage colony stimulating factor-1 receptor (CSF-1R), epidermal growth factor receptor (EGF-R), and chimeras consisting of the extracellular domain of EGF-R and the transmembrane and cytoplasmic domains of either HER2 (HER1-2) or c-kit (EK-R). All FDC-P1 transfectants proliferated in response to the corresponding growth factor in the absence of IL-3. However, only cells expressing PDGF-R, CSF-1R, and EK-R (type III RTKs) differentiated along the monocyte-macrophage lineage after treatment with their activating ligands. Analysis of proteins from these RTK-expressing cells revealed that a Mr 85,000 protein showed in vitro phosphorylation, and V8 protease peptide mapping showed that this protein was p85, the regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase). Accordingly, activation of PDGF-R-, CSF-1R-, and EK-R-expressing cells led to an increase in PI3-kinase activity. Expression of EK-R mutant Y721F, which lacked the known p85 binding site, blocked differentiation and activation of PI3-kinase, without affecting proliferation. Last, addition of wortmannin to cells expressing PDGF-R, CSF-1R, and EK-R blocked ligand-induced differentiation in a concentration-dependent manner, and this effect correlated with wortmannin's ability to inhibit PI3-kinase. Thus, ectopic expression of both type I and III RTKs could stimulate FDC-P1 proliferation in the absence of IL-3; however, only activation of type III RTKs led to differentiation via selective coupling to p85 and PI3-kinase activation.

Androstadienes↗