Biol-K 416 Lec 10

Front 1

receptor tyrosine kinases

Back 1

directly phosphorylate tyrosines on themselves and intracellular signaling proteins

Front 2

activation of RTKs

Back 2

dimerization

Front 3

PI 3-Kinase signalling

Back 3

1. promotes cell survial

2. inhibition of apoptosis (activates apoptosis-inhibitory protein)

Front 4

activation of notch

Back 4

proteolytic cleavage

Front 5

proteolytic cleavage

Back 5

activates Notch signaling

1. critical mechanism of contact-dependent cell-cell communication

2. plays a role in: neuronal dev., angiogenesis, hematopoietic stem cells expansion, cell-fate determination in mammary glands

Front 6

BMP/TGF b signalling

Back 6

smad pathway

Front 7

Wnt signalling

Back 7

1. dorsal patterning of the neural tube

2. planar cell polarity

3. axon guidance

4. maintenance and proliferation of hematopoetic stem cells

5. establishment of cancer stem cells

Front 8

hedgehog signaling

Back 8

1. development of vertebrate limbs

2. insulin production

3. angiogenesis

4. proliferation of blood progenitor cells

5. separation of trachea, esophagus, gut tube

6. induction of specific ventral neural cell populations

Front 9

FGF signalling

Back 9

1. maintance of mesoderm and neuroectoderm

2. morphogenic movements

3. anteroposterior patterning

4. somitogenesis

5. dev. of various organs

Front 10

signaling pathways we will study

Back 10

1. TGFb/BMP

2. Wnt

3. Hedgehog

4. FGF

Front 11

tyrosine-kinase-associated receptors

Back 11

1. recruit tyrosine kinases to relay signal

2. no intrinsic enzyme activity

Front 12

receptor serine/threonine kinase

Back 12

1. directly phosphorylate specific serines or threonines

2. on themselves and latent gene regulatory proteins

Front 13

histidine-kinase-associated-receptors

Back 13

1. kinase phosphorylates itself

2. transfers phosphoryl groups to a second intracellular signaling protein

Front 14

receptor guanylyl cylcases

Back 14

catalyze production of cGMP in cytosol

Front 15

cGMP

Back 15

acts as a intracellular mediator

Front 16

receptor-like tyrosine phosphatases

Back 16

remove phosphate groups from tyrosines of specific intracelluar signaling proteins

Front 17

dimerization

Back 17

activation of RTKs

1. inactive RTKs

2. signal molecule binds to RTKs

3. cross-phosphorylation by activated kinase domains

Front 18

docking of intracellular signaling proteins

Back 18

1. occurs on phosphotyrosines on activated RTK

2. activated signaling proteins relay signal downstream

Front 19

phosphoinositide docking sites

Back 19

catalyzed by PI 3-kinase

Front 20

notch-delta lateral inhibition

Back 20

1. nerve cell develops from epithelial cell

2. nerve cells has Notch receptor

3. Notch binds to Delta

4. inhibits epithelial cells

5. does not become neural cell

Front 21

Delta protein

Back 21

1. membrane bound

2. inhibitory signal protein

3. prevents unspecified cells from specializing (into neuronal cells)

Front 22

proteolytic cleavage pathway

Back 22

1. cleavage at site 1 in Golgi

2. transport to plasma membrane

3. binding to Delta

4. endocytosis of Delta-Notch fragment complex

5. cleavage at site 2

6. cleavage at site 3

7. Notch tail migrates to nucleus

8. Notch tail in protein complex activates gene transcription

9. transcription of Notch target genes

Front 23

TGFb superfamily

Back 23

1. TGFbs, Activins, BMPs, GDFs, Nodal

2. cell growth, differentiation, apoptosis, homeostasis

Front 24

TGFbs

Back 24

involved in bone development, hematopoesis

Front 25

BMPs

Back 25

involved in mesoderm and endoderm formation, cardiac/kidney/liver/GI development

Front 26

Nodal

Back 26

involved in primitive streak formation, mesoderm/endoderm formation

Front 27

Activins

Back 27

involved in ovulation, wound healing, morphogenesis of branching organs, neural development

Front 28

TGFb signaling pathway

Back 28

via Smad activation

1. TGFb binds

2. T2 receptor phosphorylates T1 receptor

3. phosphorylated T1 receptor recruits and phosphorylates Smad2 or Smad3

4. p-Smad2/3 dissociates from receptor

5. p-Smad2/3 oligomerizes with Smad4

6. Smad2/3-Smad4 oligomer translocates to nucleus

7. oligomer recruits other gene regulatory preins

8. oligomer activates transcription of specific target genes

9. target gene transcription

Front 29

Wnt proteins

Back 29

1. tetra-amelia

2. LRP

3. Frizzled

4. Axin

5. APC

Front 30

Tetra-amelia

Back 30

absence of limbs

Front 31

LRP

Back 31

1. bone density defects

2. vascular defects in eye

Front 32

Frizzled

Back 32

retinal angiogenesis defects

Front 33

Axin

Back 33

1, tooth agenesis

2. predisposition ot colorectal cancer

Front 34

APC

Back 34

1. polyposis coli

2. colon cancer

Front 35

Wnt/B-Catenin Signaling pathway: Without Wnt

Back 35

1. phosphorylated B-catenin is ubiquitylated and degraded in proteasomes

2. unstable B-catenin

3. Wnt Target genes off

Front 36

Wnt/B-Catenin Signaling pathway: with Wnt

Back 36

1. activated Frizzled and LRP

2. unphospyrlated B-catenin accumulates

3. B-catenin (stable) migrates to nucleus

4. displaces Groucho and assocaites with coactivator

5. transcription of Wnt target genes

Front 37

Hedgehog isoforms

Back 37

sonic

indian

desert

Front 38

SHH concentrations

Back 38

Hedgehog signalling

1. digits 1-5

2. SHH independent (pinky) - extended expression (thumb)

Front 39

no hedgehog signaling: inactive smoothened

Back 39

1. phosphorylation of Ci by PKA, GSK3, CK1

2. ubiquitylation and proteolytic processing of phosphorylated Ci protein in proteasomes

3. translocation of cleaved Ci protein into nucleus

4. hedgehog target off

Front 40

hedgehog signaling: active smoothened

Back 40

1. hedgehog signal binds to Patched and iHog

2. leads to degradation (lysosomes) of Patch

3. transport of Smoothened to plasma membrane

4. Smoothened is phosphorylated (by PKA and CK1) and recruited to (vesicle fusion) plasma membrane

5. Smoothened recruits Ci protein complex

6. inhibits Ci proteolysis

7. Ci is released from complex

8. Ci transported to nucleus

9. activate transcription

10. transcription of hedgehog target genes