Coordination of cellular-Coordination of cellular-fate processesfate processes

Dept. PhysiologyDept. PhysiologyChang Gung UniversityChang Gung University

J. K. chen, ProfessorJ. K. chen, Professor

Cellular fate processesCellular fate processes

Cells undergo various fate processes viaCells undergo various fate processes via

1. secretion of soluble signals.1. secretion of soluble signals.

2. secret insoluble signals that alter the 2. secret insoluble signals that alter the physical and chemical composition of their physical and chemical composition of their microenvironment through modifications microenvironment through modifications of the ECM.of the ECM.

3. they touch each other and communicate 3. they touch each other and communicate via direct cell-cell contact.via direct cell-cell contact.

Growth factorsGrowth factors

Growth factors may be divided into 2 grouGrowth factors may be divided into 2 groups :ps :

CytokinesCytokines – stimulate cell growth, and per – stimulate cell growth, and permit or instruct cell differentiation.mit or instruct cell differentiation.

ChemokinesChemokines -- induce and direct cell migr -- induce and direct cell migration.ation.

Growth factors commonly Growth factors commonly used in cell culturesused in cell cultures

Insulin 1922 by Banting and BestInsulin 1922 by Banting and Best NGF 1948 by BuekerNGF 1948 by Bueker EGF 1962 by CohenEGF 1962 by Cohen IGFs 1967 by Froesch et al.IGFs 1967 by Froesch et al. PDGF 1982 by Johnson et al.PDGF 1982 by Johnson et al. FGFs 1987 by GospodarowiczFGFs 1987 by Gospodarowicz 1988 by Thomas1988 by Thomas TGF-alpha 1985 by TodaroTGF-alpha 1985 by Todaro TGF-beta 1983 by Assoian et alTGF-beta 1983 by Assoian et al VEGF 2000 by Saristo et alVEGF 2000 by Saristo et al

The vascular endothelial cell growth factorsThe vascular endothelial cell growth factors

1. VEGF family : PlGF, VEGF-A through -D.1. VEGF family : PlGF, VEGF-A through -D.

2. Angiopoietin family : Ang-1 through -4.2. Angiopoietin family : Ang-1 through -4.

3. Ephrin family : at least one member is involved.3. Ephrin family : at least one member is involved.

(Ephrin-B2)(Ephrin-B2)

Yancopoulos et al., Yancopoulos et al., Nature 407 (2000) Nature 407 (2000)

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VEGFs and angiopoietins, their receptor binding specificity, and some of theiVEGFs and angiopoietins, their receptor binding specificity, and some of their endothelial effects. Neuropilin (NRP-1) functions as a co-receptor for the Vr 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 stiEGF165 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 inhibitorymulatory ligands for Tie-2, whereas Ang-2 and Ang-3 are inhibitory

Saristo et al., 2000Saristo et al., 2000

Oncogene Vol. 19Oncogene Vol. 19JKC

SCIENCE, 277, July 1997SCIENCE, 277, July 1997

Lessons from gene-knockout miceLessons from gene-knockout mice

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Hepatocyte growth factorHepatocyte growth factor

Stimulates division of hepatocytes, epidStimulates division of hepatocytes, epidermal keratinocytes, renal tubular epithermal keratinocytes, renal tubular epithelial cells, and melanocytes.elial cells, and melanocytes.

Also named as scatter factor with motilitAlso named as scatter factor with motility and morphogenic effects. It is a paracriy and morphogenic effects. It is a paracrine factor secreted by mesenchymal cells.ne factor secreted by mesenchymal cells.

It acts through cell surface tyrosine kinaIt acts through cell surface tyrosine kinase receptor. se receptor.

EGFEGF(epidermal growth factor)(epidermal growth factor)

It stimulates the proloferation ofIt stimulates the proloferation of Bone cells, smooth muscle cells, Bone cells, smooth muscle cells, epithelial cells, heart mesenchymal ceepithelial cells, heart mesenchymal ce

lls,hepatocytes, glial cells, oral mucoslls,hepatocytes, glial cells, oral mucosal cells, fibroblasts, etc.al cells, fibroblasts, etc.

PDGFPDGF(platelet-derived growth factor)(platelet-derived growth factor)

A major mitogen in serum for:A major mitogen in serum for: fibroblasts, smooth muscle cells, glial fibroblasts, smooth muscle cells, glial

cells, chondrocytes, and other mesenccells, chondrocytes, and other mesenchymal cells.hymal cells.

platelet is a rich source of PDGF.platelet is a rich source of PDGF.

FGFFGF(fibroblast growth factor)(fibroblast growth factor)

Present in both normal and tumor tissues.Present in both normal and tumor tissues.Normal tissuesNormal tissues brain, pituitary, hypothalamus, kidney, adrenal,liver, skeletal brain, pituitary, hypothalamus, kidney, adrenal,liver, skeletal

muscle, heart, cartilage, bones, and prostate etc.muscle, heart, cartilage, bones, and prostate etc.

TumorsTumors hepatoma, melanoma, mammary tumor, bladder tumor,prostahepatoma, melanoma, mammary tumor, bladder tumor,prosta

te tumor ,glioma ,neuroblastoma ,retinoblastomate tumor ,glioma ,neuroblastoma ,retinoblastoma

CellsCells endothelial cells, smooth muscle cells, nerves, fibroblasts, macendothelial cells, smooth muscle cells, nerves, fibroblasts, mac

rophages.rophages.

TGF-betaTGF-beta

Stimulates anchorage indepent cell growth Stimulates anchorage indepent cell growth in soft agar in the presence of EGF or TGF-alin soft agar in the presence of EGF or TGF-alphapha

Stimulates matrix synthesis, and inhibits deStimulates matrix synthesis, and inhibits degradation.gradation.

Regulates bone remodeling by coordinated Regulates bone remodeling by coordinated actions on chondrocytes, osteoblasts and oactions on chondrocytes, osteoblasts and osteoclastssteoclasts

Inhibits endothelial cell proliferation, yet pInhibits endothelial cell proliferation, yet promotes angiogenesis in vivo. romotes angiogenesis in vivo.

A schematic representation of IF-A schematic representation of IF-gamma signal transduction pathwaygamma signal transduction pathway

Biological functions of soluble Biological functions of soluble growth factor receptorsgrowth factor receptors

PDGF and the sis oncogenePDGF and the sis oncogene

PDGFR accept signals frPDGFR accept signals from PDGFaa,bb, and ab. om PDGFaa,bb, and ab.

Sis is an oncogene that Sis is an oncogene that encodes b chain of the Pencodes b chain of the PDGFDGF

Activation of erbB oncogeneActivation of erbB oncogene

Extracellular matrixExtracellular matrix

ECM provides tissue with mechanical ECM provides tissue with mechanical supportsupport

Provides cells with a substrate on Provides cells with a substrate on which to migrate, and a place to which to migrate, and a place to locate signals for communication.locate signals for communication.

It is dynamic and is constantly been It is dynamic and is constantly been modified.modified.

It has both structural and It has both structural and informational functions.informational functions.

Focal adhesion kinase signalingFocal adhesion kinase signaling

Malfunction in ECM signalingMalfunction in ECM signaling

Mutations in genes encoding ECM Mutations in genes encoding ECM protein, ECM remodeling protein, and protein, ECM remodeling protein, and ECM receptors causes diseases in a ECM receptors causes diseases in a variety of tissues.variety of tissues.

Both structure and the dynamic Both structure and the dynamic alteration in the ECM are important alteration in the ECM are important in maintaining the normal tissue in maintaining the normal tissue function.function.

Balance of the dynamic Balance of the dynamic degradation and synthesis of ECMdegradation and synthesis of ECM

The phosphorylation of Rb and the transcriptional activThe phosphorylation of Rb and the transcriptional activity, translocation, and degradation of P53 are regulated ity, translocation, and degradation of P53 are regulated by the interactions of integrins and ECM components.by the interactions of integrins and ECM components.

Rb regulates the expression of ECM-remodeling MMPs, and P53 Regulates the state of ECM throughTranscriptional control of ECM components and mediators of cell-ECM signaling and ECM remodeling.

Malfunctioning morphoregulatory control loop

Direct cell-cell contactDirect cell-cell contact

Cell interactions through CAMsCell interactions through CAMs

Leukocyte extravasationLeukocyte extravasation

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

Interaction between signaling Interaction between signaling mechanismsmechanisms

The three signaling mechanisms are not The three signaling mechanisms are not functioning in isolation, one must be functioning in isolation, one must be aware of potential cross-talk between aware of potential cross-talk between signaling pathways.signaling pathways.

Typically. All modes of communications Typically. All modes of communications are involved in cell and tissue processes are involved in cell and tissue processes and they thus interact or cross-talk. and they thus interact or cross-talk.

Multiple-input / single-output model Multiple-input / single-output model in FGF-2 signalingin FGF-2 signaling

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