1. Coordination of cellular-fate processes
Dept. Physiology
Chang Gung University
J. K. chen, Professor

2. Cellular fate processes
Cells undergo various fate processes via
1. 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.

3. Growth 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.

4. Growth factors commonly used in cell cultures
Insulin by Banting and Best
NGF by Bueker
EGF by Cohen
IGFs by Froesch et al.
PDGF by Johnson et al.
FGFs by Gospodarowicz
1988 by Thomas
TGF-alpha 1985 by Todaro
TGF-beta by Assoian et al
VEGF by Saristo et al

5. The 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

6. VEGFs 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 inhibitory
Saristo et al., 2000
Oncogene Vol. 19
JKC

7. Lessons from gene-knockout mice
SCIENCE, 277, July 1997
JKC

8. Hepatocyte 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.

9. EGF (epidermal growth factor)
It stimulates the proloferation of
Bone cells, smooth muscle cells,
epithelial cells, heart mesenchymal cells,hepatocytes, glial cells, oral mucosal cells, fibroblasts, etc.

10. PDGF (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.

11. FGF (fibroblast growth factor)
Present in both normal and tumor tissues.
Normal tissues
brain, pituitary, hypothalamus, kidney, adrenal,liver, skeletal muscle, heart, cartilage, bones, and prostate etc.
Tumors
hepatoma, melanoma, mammary tumor, bladder tumor,prostate tumor ,glioma ,neuroblastoma ,retinoblastoma
Cells
endothelial cells, smooth muscle cells, nerves, fibroblasts, macrophages.

12. TGF-beta
Stimulates anchorage indepent cell growth in soft agar in the presence of EGF or TGF-alpha
Stimulates matrix synthesis, and inhibits degradation.
Regulates bone remodeling by coordinated actions on chondrocytes, osteoblasts and osteoclasts
Inhibits endothelial cell proliferation, yet promotes angiogenesis in vivo.

13. A schematic representation of IF-gamma signal transduction pathway

14. Biological functions of soluble growth factor receptors

15. PDGF and the sis oncogene
PDGFR accept signals from PDGFaa,bb, and ab.
Sis is an oncogene that encodes b chain of the PDGF

16. Activation of erbB oncogene

17. Extracellular 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.

18. Focal adhesion kinase signaling

19. Malfunction 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.

20. Balance of the dynamic degradation and synthesis of ECM

21. Malfunctioning 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-remodeling
MMPs, and P53 Regulates the state of ECM through
Transcriptional control of ECM components and
mediators of cell-ECM signaling and ECM remodeling.

23. Direct cell-cell contact

24. Cell interactions through CAMs

25. Leukocyte extravasation
Activated EC express p-selectin and Paf on their surface.

26. Interaction 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.

27. Multiple-input / single-output model in FGF-2 signaling

29. 相簿
由 JKCHEN

30. Thank you !