Biol-K 324 16: Signal Transduction #2

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signaling pathways that control gene expression

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highly conserved

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surface receptor signaling

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1. receptor-associated kinase

2. cytosolic kinase

3. protein subunit dissociation

4. protein cleavage

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receptor tyrosine kinases (RTKs)

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1. regulate cell proliferation, differentiation, survival, metabolism

2. growth factor recepters (NGF, EGF, etc)

3. activate Ras/MAP kinase pathways

4. intrinsic part of the receptor

5. activate similar downstream signaling pathways

6. may dimerize during ligand binding

7. HER1-4

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RTK pathway

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1. growth factor ligand binds to receptor

2. induces dimerization and cross phosphorylation of activation lip

3. additional phosphorylation of cytoplasmic tyrosine residues

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cytokine receptors

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1. play important roles in cell growth and differentiation

2. bind JAK kinases --> STAT transcription factors

3. cytokine and cell type specific effects

4. kinase is bound tightly to cytosolic domain of receptor

5. activate similar downstream signaling pathways

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JAK kinases

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1. activate STAT transcription factors

2. bound tightly to cytokine receptors (even in absence of cytokine ligand)

3. become activated after cytokine binding and receptor dimerization

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Erythropoietin signaling

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1. cytokines provide cell survival, growth, and differentiation signals

2. allows erythroid progenitor stem cells to produce numerous new red blood cells

3. without EpoR --> red blood cells do not develop

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EpoR

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1. erythropoietin receptor

2. essential for red blood cell development

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erythropoietin signal mechanism

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1. cytokine binds to receptor

2. alters receptor conformation

3. increases activity of bound JAK kinases

4. JAK kinases tyrosine phosphorylate each other in ligand-receptor complex

5. JAK kinases are more active post phosphorylation

6. JAK kinase phosphorylate tyrosine residues in receptor cytoplasmic domain

7. SH2 and STAT recognize phosphorylated tyrosine residues in receptor cytoplasmic domain

8. STAT is phosphorylated --> dissociation, dimerization, nuclear translocation, and transcription activation

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PTB and SH2 domains

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1. receptor tyrosine kinases

2. bind to phosphotyrosine residues in RTK cytoplasmic domains

3. recruit signal complexes

4. domain binding is determined by amino acids surrounding the phosphorylated tyrosine

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STAT and pSTAT

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1. signal transduction and activation of transcription

2. pSTAT: dissociate from cytokine receptor and translocate to nucleas/activate transcription

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short-term erythropoietin signaling

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JAK2 deactivation by SHP1 phosphotase

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long-term regulation

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signal blocking and protein degradation by SOCS protein

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Ras

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key regulator of cell growth, differentiation, and survival

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Ras pathway

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1. hormone binds to receptor --> dimerization, kinase activation, cytosolic receptor tyrosine residue phosphorylation

2. GRB2 and Sos binds --> receptor inactivates Ras

3. Sos causes GDP dissociation from Ras

4. GTP binds and active Ras dissociates from Sos

5. Active Ras recruits, binds, and activates Raf

6. GTP hydrolysis --> dissociation of Ras from Raf

7. Activated MAP kinase translocates to nucleas --> activates transcription factors

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Ras signaling scaffold

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1. adds specificity

2. produce different effects downstream

3. different pathways in yeast use MAP kinase signaling pathway

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TGF-b/SMAD signaling pathway

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1. receptor complex (RI/RII/RIII) assembles in response to TGF binding

2. RII phosphorylates and activates RI

3. R-Smads are phosphorylated --> exposes NLS

4. co-SMADS bind ot phosphorylated R-SMADs

5. bind R-SMADs/co-SMAd complex --> facilitate nuclear transport

6. SMADs interact with other transcription factors --> activate target genes

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RI/RII (TGF/SMAD pathway)

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1. serine/threonine kinases

2. RII is constitutively on

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R-SMADs

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1. associated with receptor complex

2. when phosphorylated, expose NLS

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co-SMADS

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bind to the phosphorylated R-SMADs

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importins

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1. bind R-SMADs/co-SMAd complex

2. facilitate nuclear transport

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Wnt

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1. controls development (brain, limb patterning, organogenesis)

2. oncogenes

3. secreted glycoprotein that binds to Frizzled and LRP

4. induces accumulation of beta-catenin and nuclear translocation

5. secreted protein that contain lipid anchors that tether them to cell membranes --> reduces signaling ragnes

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Frizzled

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Wnt receptor

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Wnt/Fz complex

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1. binds Axin

2. disrupts the beta-catenin degradation complex

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beta-catenin/TCF complex

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1. in the nucleas

2. activate specific genes

3. Wnt signaling

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Mammalian hedgehog genes

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1. desert (DHH)

2. indian (IHH)

3. sonic (SHH)

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sonic hedgehog

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most studied mammalian hedgehog gene

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absence of hedgehog signal

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two receptor proteins are in different compartmetns

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hedgehog receptor proteins and location in absence of hedgehog signal

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1. Ptc (in plasma membrane when hedgehog is absent)

2. Smo (in endosome when hedgehog is absent)

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hedgehog signaling (transcription activation)

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1. hedgehog ligand binds to Ptc

2. induces Smo translocation from endosomes to plasma membrane

3. Smo receptor complex binds Fu/Cos2 --> dissociates Ci and microtubules

4. Ci is phosphorylated and partially degraded

5. Ci fragment translocates to nucleus

6. activates target gene transcription

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Fu/Cos2/Ci

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1. cytosolic complex in hedgehog signaling

2. bound to microtubules

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hedgehog signaling (transcription repression)

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1. cytosolic complex bound to microtubules

2. Ci is phosphorylated and partially degrade

3. Ci fragment translocates to nucleus

4. Ci fragment translocates to nucleus

5. activates target gene transcription

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protein cleavage

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used to:

1. remove a repressor

2. mobilize a protein domain

3. activate protein activity

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NF-kappaB pathway

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produces various signals and responses

1. stress, bacteria, etc. activate pathway

2. degradation of I-kappaBalpha releases NF-kappaB --> exposes NLS

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Notch/Delta signaling

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1. utilizes protein cleavage mechanisms in signaling pathways

2. juxtacrine signaling

3. Delta ligand is expressed in a cell adjacent to a Notch receptor expressing cell

4. induces ADAM10 --> cleaves Notch extracellular domain

5. gamma-secretase cleaves the Notch cytoplasmic domain

6. translocates to nuclease --> activates transcription of target genes

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ADAM10

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matric metalloproteinase

1. induced by Notch/Delta interaction

2. cleaves the Notch extracellular domain

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gamma-secretase

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1. cleaves Notch cytoplasmic domain

2. translocates to nucleus

3. activates target gene transcription

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classes that activate tyrosine kinases

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1. receptor tyrosine kinases (RTK)

2. cytokine receptors

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ligand binding

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1. triggers formation of functional dimeric receptors

2. needed in activation of receptor-associated kinase

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HER2

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1. RTK receptor

2. does not bind ligand

3. forms active heterodimers with ligand-bound monomers of other three HER proteins

4. overexpression is implicated in breast cancer

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erythropoietin

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1. cytokine secreted by kidney cells

2. promotes proliferation and differentiation of progenitor cells

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JAK/STAT pathway

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operates downstream from all cytokine receptors and some RTKs

1. STAT monomers bound to phosphotyrosines on receptors are phosphorylated by JAKs

2. dimerize and translocate to nucleus

3. activate transcription

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what is the best way to reduce the number of RTK and cytokine receptors on cell surface?

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1. endocytosis (receptor-hormone complexes)

2. degradation (in lysosomes)

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reducing RTK and cytokine receptors on cell surface does what?

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decrease sensitivity of cells to many peptide hormones

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cytokine receptor signaling termination

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by SHP1 and SOCs

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SHP1

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1. phosphotyrosine phosphatase

2. terminates cytokine receptor signaling

3. works in conjunction with SOCS proteins

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SOCS proteins

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1. terminates cytokine receptor signaling

2. works in conjunction with SHP1

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TGF-beta monomers

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1. stored in an inactive form on the cell surface or extracellular matrix

2. release of active monomers leads to formation of functional homodimers and heterodimers

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what causes release of active TGF-beta monomers

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protease digestion

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Oncoproteins

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1. ex: Ski and SnoN

2. act as negative regulators of TGF-beta signaling

3. inhibit transcription mediated by the Smad 2/3/4 complex

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I-Smads

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1. ex: Smad7

2. act as negative regulators of TGF-beta signaling

3. inhibit transcription mediated by the Smad 2/3/4 complex

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TGF-beta

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1. generally inhibits cell proliferation

2. loss of components leads to abnormal cell proliferation and malignancy

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signaling pathways with ubiquitination and proteolysis of target protein

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1. irreversible or only slowly reversible

2. target proteins can be either a transcription factor or an inhibitor of a transcription factor

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hedgehog

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1. functions as a morphogen during development

2. mutations can cause cancer

3. secreted protein that contain lipid anchors that tether them to cell membranes --> reduces signaling ranges

4. hedgehog signal acts through Smoothened or Patched

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LRP

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1. Wnt co-receptor

2. intracellular complex containing beta-catenin

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beta-catenin

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1. Wnt binding promotes stability and nuclear translocation

2. directly or indirectly promotes activation of TCF transcription factor

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Patched

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intracellular complex containing Ci transcription factor

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Ci

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1. contained in Patched

2. activating form is generated in presence of hedgehog

3. repressing form is generated in absence of hedgehog

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Patched and Smoothened

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1. facilitate hedgehog signaling

2. change subcellular location in response to hedgehog binding to Patched

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Hh signaling

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1. requires primary cilia and intraflagellar transport proteins

2. Patch localizes to the ciliary membrane in absence of Hh

3. Smo moves to cilia when Hh is present

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NF-kappaB

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1. transcription factor

2. regulates genes that permit cells to respond to infection and inflammation

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NF-kappaB in unstimulated cells

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1. localized in cytosol

2. bound to inhibitor protein I-kappaBetaalpha

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I-kappaBetaalpha

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1. inhibitor proteins

2. NF-kappaB binds to it in unstimulated cells

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active NF-kappaB

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1. released by phosphorylation-dependent ubiquitination and degradation of I-kappaBetaalpha

2. translocated to nucleus

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polyubiquitin chains

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1. linked to activated IL-1 receptor

2. form scaffold that brings TAK1 kinase near its subsrate

3. allows signals to be transmitted from the receptor to downstream components of NF-kappaB pathway

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TAK1 kinase substrate

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I-kappaB

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EGFs

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1. synthesized as transmembrane proteins

2. regulated cleavage of precursor near plasma membrane by MMP

3. releases active molecules into extracellular space to distance cells

4. cleavage is catalyzed by ADAMs

Notch

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Notch receptor

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1. binds to Delta ligand

2. undergoes two proteolytic cleavages

3. released Notch segment translocates into nucleus and modulates transcription of target genes

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gamma-secretase

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1. catalyzes the regulated intramembrane of proteolysis of Notch

2. participates in cleavage of amyloid precursor protein (APP) into peptides that form plaques (Alzheimer's)

Notch

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APP

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1. amyloid precursor protein

2. form plaques related to Alzheimer's

Notch

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insig-1(2)/SCAP/SREBP pathway

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1. active nSREBP transcription factor is released form the Gogli via intramembrane proteolysis when cellular cholesterol is low

2. stimulates expression of genes encoding proteins that function in cholesterol biosynthesis and cellular import of cholesterol

3. when cholesteral is high, SREBP is retained in ER membrane complexed with insig-1(2) and SCAP

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HMG-CoA reductase

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cholesteral biosynthesis protein

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LDL receptor

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cholesterol cellular import protein