Cell signaling ii signal transduction pathways
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Cell Signaling II Signal Transduction pathways. Cell Biology Lecture 13. Readings and Objectives. Reading Russell Chapter 8 (not sufficient) Cooper: Chapter 15 Topics Lecture 12 Signaling Molecules and Their Receptors Functions of Cell Surface Receptors Lecture 13

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Cell Signaling II Signal Transduction pathways

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Cell signaling ii signal transduction pathways

Cell SignalingIISignal Transduction pathways

Cell Biology

Lecture 13


Readings and objectives

Readings and Objectives

  • Reading

    • Russell Chapter 8 (not sufficient)

    • Cooper: Chapter 15

  • Topics

    Lecture 12

  • Signaling Molecules and Their Receptors

  • Functions of Cell Surface Receptors

    Lecture 13

  • Pathways of Intracellular Signal Transduction

  • Signal Transduction and the Cytoskeleton

  • Signaling Networks


Intracellular signal transduction pathways

Intracellular Signal Transduction Pathways

Intracellular signal transduction- chain of reactions, transmits signals/cell surfaceintracellular targets

First studied for epinephrine

Signals glycogen breakdown to glucose

Earl Sutherland (1958): action of epinephrine was mediated by an increase in cyclic AMP (cAMP)

Concept: cAMP is a second messenger

Noble prize 1971

1915-1974


Camp signal transduction pathways

cAMP Signal Transduction Pathways

Epinephrine receptor coupled to adenylylcyclase via a G protein increasing the concentration of cAMP

cAMP signaling & cell responses

Metabolic regulation

Cytosolic Protein Kinase A activation (PKA)

tetramer of regulatory and catalytic subunits, ie R2C2 (inactive)

cAMP binding of “R” dissociation of catalytic subunits (active)

A serine/threoninekinaseActivation or inactivation of substrate proteins

PKA activation


Camp signal transduction pathways1

cAMP Signal Transduction Pathways

Phosphorylation of two downstream enzymes:

Glycogen synthase inactivated glycogen synthesis↓

Phosphorylase kinase activated phosphorylates Glycogen phosphorylase (active) Glu-1P↑


Camp signal transduction pathways2

cAMP Signal Transduction Pathways

2. Gene regulation

Increased cAMP activate transcription

Free PKA C-subunit translocated to the nucleus

binds Genes containing a regulatory sequence—the cAMP response element, or CRE

phosphorylates the transcription factor CREB (CRE-binding protein).

Recruits RNA polymerase

expression of cAMP-inducible genes

Proliferation, differentiation, memory, cognition

Review article: Transcriptional regulation by cAMP


Camp signal transduction pathways3

cAMP Signal Transduction Pathways

Protein phosphorylation is reversed by protein phosphatases

terminates responses initiated by receptor activation of protein kinase


Secondary messenger dag and ip3 signaling

Secondary messenger DAG and IP3 signaling

PLC-γ binds receptor protein tyrosine kinases via SH2 domain phosphorylated (active)

PLC- γ stimulates hydrolysis of PIP2to DAG and IP3 (how?)

DAG and IP3 are secondary messengers

IP3 regulates Ca2+

DAG activates PKC family

PLC=Phospholipase C

PIP2: Phosphatidylinositol 4,5-bisphosphate

IP3: Inositol 1,4,5-trisphosphate

DAG:Diaceyl glycerol


Secondary messenger dag and ip3 signaling1

Secondary messenger DAG and IP3 signaling

PLC-γ binds receptor protein tyrosine kinases via SH2 domain phosphorylated (active)

PLC- γ stimulates hydrolysis of PIP2to DAG and IP3 (how?)

DAG and IP3 are secondary messengers

IP3 regulates Ca2+

DAG activates PKC family

PLC=Phospholipase C

PIP2: Phosphatidylinositol 4,5-bisphosphate

IP3: Inositol 1,4,5-trisphosphate

DAG:Diaceyl glycerol


Secondary messenger dag and ip3 signaling2

Secondary messenger DAG and IP3 signaling

DAG remains associated with the plasma membrane and activates protein-serine/threonine kinases of the protein kinase C family.

IP3 , a small polar molecule, released to the cytosol

Stimulates release of Ca2+ from the ER by binding to receptors that are ligand-gated Ca2+ channels


Secondary messenger dag and ip3 signaling3

Secondary messenger DAG and IP3 signaling

Calmodulin is activated when Ca2+ concentration increases

CaM kinase family are activated by Ca2+/calmodulin

they phosphorylate and activate other proteins such as,

protein kinases, phosphatases, metabolic enzymes, ion channels, and transcription factors (eg CREB)

Alsoregulates synthesis and release of neurotransmitters


Secondary messenger dag and ip3 signaling4

Secondary messenger DAG and IP3 signaling

nonmuscle cells and smooth muscles, contraction is regulated by phosphorylation of myosin light chain

catalyzed by myosin light chain kinase, which is regulated by the Ca2+ binding protein calmodulin


Secondary messenger dag and ip3 signaling5

Secondary messenger DAG and IP3 signaling

Increased [Ca2+ ] signals further release of Ca2+ from the ER by opening Ca2+ channels (ryanodine receptors) in the ER membrane.

Ca2+ is a versatile second messenger that controls a wide range of cellular processes

These pathways function coordinately to regulate many cellular responses


Cell signaling ii signal transduction pathways

PIP2 is also the start of another signaling pathway

PIP2 is phosphorylated by phosphatidylinositide (PI) 3-kinase

This yields a second messenger, phosphatidylinositol 3,4,5-trisphosphate (PIP3)

PI 3/Akt signaling pathway


Cell signaling ii signal transduction pathways

PIP3 targets a protein-serine/threonine kinase called Akt and also binds protein kinase PDK1

Activation of Akt also requires protein kinase mTOR (in a complex called mTORC2) which is also stimulated by growth factor

PI3/Akt signaling pathway

mTOR: mammalian target of rapamycin

PDK1:phosphoinositide dependent protein kinase-1

GSK3: glycogen synthase kinase 3

Bad: Bcl2 associated death promoter (promotes apoptosis)


Cell signaling ii signal transduction pathways

Akt phosphorylates several target proteins, transcription factors, and other protein kinases

Transcription factors include members of the Forkhead or FOXO family

If growth factors are not present, Akt is not active

FOXO travels to the nucleus, stimulates transcription of genes that inhibit cell proliferation, or induce cell death

PI3/Akt signaling pathway


Cell signaling ii signal transduction pathways

When growth factors attached to receptor/tyrosine kinases

Akt is phosphorylated (active)

Akt phosphorylation of FOXO sequesters it in inactive form

Akt inhibits GSK-3, the general inhibitor of translation

Inhibition of GSK-3 relieves translation

Cells are prepared to proliferate

PI3/Akt signaling pathway


Cell signaling ii signal transduction pathways

MAP kinases (mitogen-activated protein kinases) are protein-serine/threonine kinases

Conserved across eukaryotic cells; three groups of MAP kinases

MAP Kinase Signaling Pathways


Cell signaling ii signal transduction pathways

ERK (extracellular signal-regulated kinase) family, first to be identified in MAPKs

regulation of meiosis, mitosis, cell proliferation and differentiation

Ligands: growth factors, cytokines and viral infection, carcinogenic chemicals

ERK Signaling Pathway


Cell signaling ii signal transduction pathways

ERK activation mediated by Ras, Raf, MEKkinase cascade

Activation of Rasactivation of Rafprotein serine/threoninekinase

Rafphosphorylates and activates a second protein kinase called MEK(MAPK/ERK Kinase)

MEK activates ERK transcriptional activation

ERK Signaling Pathway


Cell signaling ii signal transduction pathways

Ras: guanine nucleotide-binding protein that function like αsubunits of G proteins

Ras is activated by guanine nucleotide exchange factors (GEF)

Sos=specific GEF for Ras

GTPase-activating proteines GTP hydrolysis

Ras-GDP becomes inactive

ERK Signaling Pathway


Cell signaling ii signal transduction pathways

Grb2: SH2 domain containing protein associated with Sos

RPTK activation by ligand recruits Grb2/Sos to membrane

Grb2/Sos contacts Ras-GDP GTP replaces GDP in Ras

Ras-GTP activated and phosphorylatesRaf

Raf initiates a protein kinase cascade ERK activation

ERK Signaling Pathway


Cell signaling ii signal transduction pathways

ERK goes to the nucleus, phosphorylates Elk-1

transcriptional induction of immediate-early genes (~ 100 genes)

serum response element (SRE), recognized by transcription factors serum response factor (SRF) and Elk-1

immediate-early genes encode transcription factors

Activate downstream genes called secondary response genes

Cell proliferation and growth

ERK Signaling Pathway


Cell signaling ii signal transduction pathways

Specificity of MAP kinase signaling is maintained in part by their physical association on scaffold proteins

For example, the KSR scaffold protein organizes ERK and its upstream activators Raf and MEK into a signaling cassette

ERK Signaling Pathway


Cell signaling ii signal transduction pathways

Direct signaling from receptor to nucleus

Ligand: cytokines

Receptors: Janus Kinases (JAK), nonreceptor protein-tyrosine kinase

STAT: Signal Tansducer & Activators of Transcription

Transcription factors, contain SH2 domains that mediate binding to phosphotyrosine sequences

STATs activated, dimerized, translocate to nucleus

Activate transcription

JAK/STAT Pathway


Cell signaling ii signal transduction pathways

direct cell-cell interactions during development

Notch a receptor for signaling by transmembrane proteins (e.g., Delta) on adjacent cells

Ligand binding proteolytic cleavage of cytosolic domain of Notch

translocated into the nucleus

converts a transcription factor (CSL in mammals) from a repressor to an activator

Downstream genes code for other transcriptional factors

Cell developmental differentiation

Notch Pathway

Minireview: Notch signaling


Cell signaling ii signal transduction pathways

binding of integrins to the extracellular

activation of FAK( focal adhesion kinase), a nonreceptor protein-tyrosine kinase

provides binding sites for Grb2-Sos complex, leading to activation of Ras/ERK, PI 3-kinase

Integrins and Signal Transduction


Cell signaling ii signal transduction pathways

Rho subfamily of small GTP-binding proteins (Rho, Rac, and Cdc42) regulate organization of the actin cytoskeleton

Rho family proteins promote actin polymerization

Integrins and Signal Transduction


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