Presentation on theme: "Coordination of cellular-fate processes"— Presentation transcript:
1Coordination of cellular-fate processes Dept. PhysiologyChang Gung UniversityJ. K. chen, Professor
2Cellular fate processes Cells undergo various fate processes via1. secretion of soluble signals.2. secret insoluble signals that alter the physical and chemical composition of their microenvironment through modifications of the ECM.3. they touch each other and communicate via direct cell-cell contact.
3Growth factors Growth factors may be divided into 2 groups : Cytokines – stimulate cell growth, and permit or instruct cell differentiation.Chemokines -- induce and direct cell migration.
4Growth factors commonly used in cell cultures Insulin by Banting and BestNGF by BuekerEGF by CohenIGFs by Froesch et al.PDGF by Johnson et al.FGFs by Gospodarowicz1988 by ThomasTGF-alpha 1985 by TodaroTGF-beta by Assoian et alVEGF by Saristo et al
5The vascular endothelial cell growth factors 1. VEGF family : PlGF, VEGF-A through -D.2. Angiopoietin family : Ang-1 through -4.3. Ephrin family : at least one member is involved.(Ephrin-B2)Yancopoulos et al., Nature 407 (2000)JKC
6VEGFs and angiopoietins, their receptor binding specificity, and some of their endothelial effects. Neuropilin (NRP-1) functions as a co-receptor for the VEGF165 isoform, P1GF-2, VEGF-B and VEGF-E. Ang-1 and Ang-4 are stimulatory ligands for Tie-2, whereas Ang-2 and Ang-3 are inhibitorySaristo et al., 2000Oncogene Vol. 19JKC
7Lessons from gene-knockout mice SCIENCE, 277, July 1997JKC
8Hepatocyte growth factor Stimulates division of hepatocytes, epidermal keratinocytes, renal tubular epithelial cells, and melanocytes.Also named as scatter factor with motility and morphogenic effects. It is a paracrine factor secreted by mesenchymal cells.It acts through cell surface tyrosine kinase receptor.
9EGF (epidermal growth factor) It stimulates the proloferation ofBone cells, smooth muscle cells,epithelial cells, heart mesenchymal cells,hepatocytes, glial cells, oral mucosal cells, fibroblasts, etc.
10PDGF (platelet-derived growth factor) A major mitogen in serum for:fibroblasts, smooth muscle cells, glial cells, chondrocytes, and other mesenchymal cells.platelet is a rich source of PDGF.
11FGF (fibroblast growth factor) Present in both normal and tumor tissues.Normal tissuesbrain, pituitary, hypothalamus, kidney, adrenal,liver, skeletal muscle, heart, cartilage, bones, and prostate etc.Tumorshepatoma, melanoma, mammary tumor, bladder tumor,prostate tumor ,glioma ,neuroblastoma ,retinoblastomaCellsendothelial cells, smooth muscle cells, nerves, fibroblasts, macrophages.
12TGF-betaStimulates anchorage indepent cell growth in soft agar in the presence of EGF or TGF-alphaStimulates matrix synthesis, and inhibits degradation.Regulates bone remodeling by coordinated actions on chondrocytes, osteoblasts and osteoclastsInhibits endothelial cell proliferation, yet promotes angiogenesis in vivo.
13A schematic representation of IF-gamma signal transduction pathway
14Biological functions of soluble growth factor receptors
15PDGF and the sis oncogene PDGFR accept signals from PDGFaa,bb, and ab.Sis is an oncogene that encodes b chain of the PDGF
17Extracellular matrix ECM provides tissue with mechanical support Provides cells with a substrate on which to migrate, and a place to locate signals for communication.It is dynamic and is constantly been modified.It has both structural and informational functions.
19Malfunction in ECM signaling Mutations in genes encoding ECM protein, ECM remodeling protein, and ECM receptors causes diseases in a variety of tissues.Both structure and the dynamic alteration in the ECM are important in maintaining the normal tissue function.
20Balance of the dynamic degradation and synthesis of ECM
21Malfunctioning morphoregulatory control loop The phosphorylation of Rb and the transcriptional activity, translocation, and degradation of P53 are regulated by the interactions of integrins and ECM components.Rb regulates the expression of ECM-remodelingMMPs, and P53 Regulates the state of ECM throughTranscriptional control of ECM components andmediators of cell-ECM signaling and ECM remodeling.
25Leukocyte extravasation Activated EC express p-selectin and Paf on their surface.
26Interaction between signaling mechanisms The three signaling mechanisms are not functioning in isolation, one must be aware of potential cross-talk between signaling pathways.Typically. All modes of communications are involved in cell and tissue processes and they thus interact or cross-talk.
27Multiple-input / single-output model in FGF-2 signaling