Cell Cell Communication-IICommunication-II

(Fall 2010)(Fall 2010)

Pin Ling ( 凌 斌 ), Ph.D.

Department of Microbiology & Immunology, NCKU

ext 5632; lingpin@mail.ncku.edu.tw

Reference:

“Mechanisms of Cell Communication”, The Cell (5th edition), Chapter 15

Outline General principles of cell communication

Signaling through G-protein-coupled cell surface receptors (GPCRs) and small intracellular mediators

Signaling through enzyme-coupled cell-surface receptors

Signaling pathways dependent on regulated proteolysis of latent gene regulatory proteins

Signaling in plants

Six major classes of enzyme-Six major classes of enzyme-coupled receptorscoupled receptors

1. Receptor Tyrosine Kinases (RTKs)

2. Tyrosine kinase-associated receptors: No intrinsic enzyme activity.

3. Receptor Ser/Thr kinases

4. Histidine-kinase associated receptors : two-component signaling pathway

5. Receptor guanylyl cyclases

6. Receptor Tyr phosphatases

RTK Subfamilies (16): RTK Subfamilies (16):

60 human RTKs60 human RTKs

Some growth factors or Some growth factors or cytokines act via RTKscytokines act via RTKs

Signaling via RTKsSignaling via RTKs

1. Activated RTKs phosphorylate themselves.

2. Phosphorylated Tyr residues on RTKs => Docking sites

3. Proteins w/ SH2 domain (PTB domain) bind to phophorylated Tyr resides.

4. Ras, a family of monomeric GTPase, acts downstream of many RTKs.

5. Ras activates a MAPK signaling module via adaptors & GEFs.

Activation of Activation of RTKsRTKs via via dimerizationdimerization

Intracellular domains of Intracellular domains of activated RTKs provide activated RTKs provide

“docking sites’“docking sites’

Figure 15-55a Molecular Biology of the Cell (© Garland Science 2008)

Binding of SH2-containing Binding of SH2-containing proteins to activated PDGF proteins to activated PDGF

receptor receptor

SH2 domains recognize phospho-SH2 domains recognize phospho-Tyr in the context of flanking Tyr in the context of flanking sequencessequences

Ras superfamily of monomeric Ras superfamily of monomeric GTPasesGTPases

Sev RTK activates Ras in the Sev RTK activates Ras in the flyfly

Ras activates the MAPK Ras activates the MAPK pathwaypathway

Activation of ERK/MAPK at various intracellular compartments-I

Scaffold proteins in formation Scaffold proteins in formation of signaling complexesof signaling complexes

Rho family GTPases couple Rho family GTPases couple surface receptors to the surface receptors to the

cytoskeletoncytoskeleton

The downstream pathways The downstream pathways activated by GPCRs & RTKsactivated by GPCRs & RTKs

PI3K (Phosphoinositide 3-PI3K (Phosphoinositide 3-kinase) Signalingkinase) Signaling

1. PI3K is involved in downstream pathways of many “Growth Factor Receptors”.

2. PI3K mainly phosphorylates inositol phospholipids

=> Docking sites on the plasma membrane.

3. PI3K activates the downstream AKt-mTOR pathway => Regulate cell survival & proliferation.

4. Deregulation of this pathway is often found in many cancer cells.

Generation of PI docking sites Generation of PI docking sites by PI3Kby PI3K

Cell survival via PI3K Cell survival via PI3K signalingsignaling

Cell growth via PI3K Cell growth via PI3K signalingsignaling

Tyrosine kinase-associated Tyrosine kinase-associated receptor signalingreceptor signaling

1. Many cell surface receptors depend on Tyr phosphorylation but lack a Tyr kinase domain, e.g. Cytokine receptors, Integrins, …etc

2. These receptors act through Cytoplasmic Tyrosine

Kinases, e.g. Src family kinases, FAK, ….etc.

3. Cytokine receptor activate the JAK-STAT pathway.

4. Tyr Phosphatases reverse Tyr phosphorylation on various Tyr-phosphorylated proteins.

5. Tyr phosphatases have transmembrane & cytoplasmic forms.

Cytokine signaling via the Cytokine signaling via the JAK-STAT pathwaysJAK-STAT pathways

Table 15-6 Molecular Biology of the Cell (© Garland Science 2008)

Cytokine Receptor Cytokine Receptor signaling via the JAK-STAT signaling via the JAK-STAT

pathways-IIpathways-II

1. TGFsuperfamily consists of various mediators to regulate cell proliferation, specification & differentiation, e.g. TGFb/activin family, BMP (bone morphogenetic protein) family.

2. All these mediators act via Ser/Thr kinase-coupled

receptors.

3. Activated receptors trigger the Smad pathway.

Transforming growth factor-Transforming growth factor- (TGF (TGF) Superfamily) Superfamily

TGF-beta signaling TGF-beta signaling pathwaypathway

Ser/Thr and Tyr protein Ser/Thr and Tyr protein kinases are structurally kinases are structurally

relatedrelated

1. In bacteria, chemotaxis response is mediated by Histidine kinase associated receptors.

2. These receptors activate a two-components signaling pathway, also seen in yeasts & plants.

3. Histidine kinase-associated chemotaxis receptors

regulates flagella movements in a straight line or

tumbling.

Bacterial chemotaxis via Bacterial chemotaxis via Histidine kinase-associated Histidine kinase-associated

receptorsreceptors

Flagella movement during Flagella movement during E. Coli swimmingE. Coli swimming

Chemotaxis Chemotaxis receptors receptors control control flagella flagella movementmovementCheW: AdaptorCheA: His kinaseCheY: Effector/ Phosphatase

OutlineOutline General principles of cell communication

Signaling through G-protein-coupled cell surface receptors (GPCRs) and small intracellular mediators

Signaling through enzyme-coupled cell-surface receptors

Signaling pathways dependent on regulated proteolysis of latent gene regulatory proteins =>Irreversible

Signaling in plants

Signaling via Notch Signaling via Notch Receptor Protein Receptor Protein

1. Notch signaling is involved in regulating cell fates & development.

2. Role of Notch in nerve cell production: Neighbor cell |= Precursor cell => Nerve cell

3. Signaling between adjacent cells via Notch & Delta (or other related ligands).

4. Notch is a single-pass transmembrane protein undergoing proteolytic process to function.

5. Deregulated Notch signaling is often found in cancer development.

““Lateral inhibition” of nerve Lateral inhibition” of nerve cell development via Notch cell development via Notch

signaling signaling

Proteolytic cleavage of Notch Proteolytic cleavage of Notch & its signaling& its signaling

Wnt/Wnt/-Catenin signaling-Catenin signaling

Activation of NF-Activation of NF-B pathway B pathway by TNFby TNF

Negative feedback control Negative feedback control

& NF-& NF-B oscillationsB oscillations

OutlineOutline General principles of cell communication

Signaling through G-protein-coupled cell surface receptors (GPCRs) and small intracellular mediators

Signaling through enzyme-coupled cell-surface receptors

Signaling pathways dependent on regulated proteolysis of latent gene regulatory proteins =>Irreversible

Signaling in plants

Signaling in PlantsSignaling in Plants

1. Multicellularity & Cell communication evolved independently in Plants & Animals.

2. Receptor Ser/Thr kinases are the largest family in plants.

3. Various plant hormones (growth factors) regulate plant development, e.g. ethylene, Auxin,….etc.

4. Signaling in plants mainly come from genetic studies on Arabidopsis.

Divergence of plant & Divergence of plant & animal lineageanimal lineage

Clavata1/Clavata2 (Clv1/Clv2)Clavata1/Clavata2 (Clv1/Clv2) : : Leucine-rich repeat receptor (LRR) Leucine-rich repeat receptor (LRR) kinaseskinases

Ethylene-Ethylene-mediated growth mediated growth control:control:

1. Promote fruit ripening, leaf abscission, & senescence.

2. Germinating seedling:(1) Thicken its stem(2) Shield its tip of the

shoot(3) Avoid obstacle

Ethylene Signaling Ethylene Signaling PathwayPathway

Raf-like

Photochromes mediate a light response

““Discussion” to be Discussion” to be continuedcontinued