cell-cell communication

types of cell signaling

paracrine, autocrine, and juxtracrine

paracrine

cells send out a signal to be received by competent cells

autocrine

variation where cell may respond to its own signal

juxtracrine

variation where cells must be in direct contact (hyperlocal)

endocrine signaling

hormone signaling

how does endocrine signaling work

travels through the blood

does endocrine signaling have a concentration gradient

no

does paracrine signaling have a concentration gradient

yes

induction

cells attempt to trigger a change in the responding cells

competence

not all cells may be able to respond to the signal; cells that can are competent

ligand

signal molecule who’s binding triggers a change in the receptor

ligand binding

activation typically involves conformational change, cleavage, and/or phosphorylation

transduction cascade

serial activation of intracellular signaling molecules

cell response

typically activation of a transcription factor and ensuring activation of new gene expression

cell signaling process

1. ligand binding activates the receptor (outside cell membrane)

2. activated receptor activates intracellular signaling molecules (between cell and nucleus membrane)

3. intracellular signaling activates effector - often a transcription factor (inside nuclear membrane)

4. activated transcription factor binds to DNA and activates transcription of a target gene

step one of cell signaling process

ligand binding activates the receptor (outside cell membrane)

step two of cell signaling process

activated receptor activates intracellular signaling molecules (between cell and nuclear membrane)

step three of cell signaling process

intracellular signaling activates effector - often a transcription factor (inside nuclear membrane)

step four of cell signaling process

activated transcription factor binds to DNA and activates transcription of a target gene

target gene

genes that have transcription activated when a signal pathway is activated

label the effector

D

label the ligand

A

label the receptor

B

label the intracellular signaling molecules

C

key pathways

hedgehog, Wnt/wingless, TGF-β/BMP, FGF/RTK, and notch

hedgehog ligand

hedgehog (Hh), sonic hedgehog (Shh), indian hedgehog (Ihh)

hedgehog effector

transcription factor Ci (flies) or Gli (vertebrates)

what happens in the absence of hedgehog ligand

Ci/Gli is cleaved and cannot activate gene expression

where was the Hh pathway first discovered

Drosophila

what was Hh named after

mutant phenotype (embryo has extra bristles)

what is Hh role in development

important for roles in development of nervous system (spinal cord development and eye development) and limb development

what can impaired Hh signaling cause

cyclopia

is hedgehog paracrine, autocrine, or juxtracrine

paracrine

what is the hedgehog pathway target gene

Hh-target genes

Wnt ligand

Wnt (wingless/wg in flies)

Wnt effector

β-catenin transcription factor

what happens in absence of Wnt ligand

β-catenin is continually degradeed in the cytoplasm

what happens in the presence of Wnt

β-catenin is stabilized and can enter the nucleus to activate transcription of Wnt-target gene

what happens in the presence of the hedgehog ligand

Ci/Gli is not cleaved and can enter the nucleus, bind to enhancers, and activate expression of the Hh-target gene

what is the function of the Wnt pathway

important roles in early embryonic development (setting up early signaling centers like the Organizer) and kidney development

what do Wnt mutant mice lack

kidneys

is the Wnt pathway paracrine, autocrine, or juxtracrine

paracrine

what are the Wnt target genes

Wnt-target gene

TGF-β/BMP pathway ligand

TGF-β, BMPs, Nodal, Activin

TGF-β/BMP pathway internal signaling molecule

transcription factor called “Smads”

what does TGF-β/BMP ligand binding trigger

phosphorylation cascade to activate Smads

what happens in the absence of TGF-β/BMP ligands

Smads are not phosphorylated and are therefor inactive

what role does the TGF-β/BMP pathway play

important in early embryonic patterning (helps set up early patterning centers like the Organizer), limb development, and patterning of the nervous system

seen in BMP mutants

digit patterning defects (defect where digits don’t know which digit its meant to be)

is TGF-β/BMP pathway paracrine, autocrine, or juxtracrine

paracrine

FGF/RTK pathway ligands

growth factors (GFs) such as FGF, EGF, VEGF, etc.

FGF/RTK pathway receptors

growth factor receptors (GFRs) such as FGFR, EGFR, VEGFR, etc.

what internal signaling molecules are often mutated in human cancer

Ras and Raf

what does FGF/RTK ligand binding trigger

phosphorylation of internal signaling molecules

what pathways trigger phosphorylation

FGF/RTK pathway and TGF-β/BMP pathway

FGF/RTK effector proteins

transcription factors

FGF/RTK target genes

pro-proliferation genes

FGF/RTK role

important in kidney development, vasculogenesis, and craniofacial development

what does impaired vasculogenesis in VEGF mutant look like

swelling of the limbs

is the FGF/RTK pathway paracrine, autocrine, or juxtracrine

paracrine

is the notch pathway paracrine, autocrine, or juxtracrine

juxtracrine

notch pathway ligands

delta, jagged

what type of protein are notch pathway ligands

membrane proteins

notch pathway receptor

notch

what happens in the absence of the notch pathway ligand

the notch protein is embedded in the membrane

what happens in when the notch pathway ligand binds

the interior portion of the notch protein is cleaved and is free to travel to the nucleus, where it acts as a transcription factor

what is the role of the notch pathway

important for somite/vertebral development (backbone) and hematopoiesis

what can a mutation in the notch pathway lead to

vertebral defects such as “butterfly” vertebrae

when was the Townes and Holtfreter experiment

1995

what was the Townes and Holtfreter experiment

took 2 different frog species’ embryos and spliced them together (epithelial from one and neural from another), mixed them together and the cells eventually self sorted to a neural center with an epithelial shell

Which of the pathways discussed today (Hh, Wnt/Wg, TGF-β/BMP, FGF/RTK, and Notch) is NOT a paracrine signaling pathway

notch - it is juxtracrine

What is the transcription factor in the Hh pathway

Ci/Gli

What is the transcription factor in the Wnt/Wg pathway

β-catenin

“Smads” are intracellular signaling molecules in which pathway

TGF-β/BMP

which pathway is often mutated in human cancers

FGF/RTK - bc of its association with growth factors

cadherins

proteins on the surface of cells that mediate cell-cell attraction/repulsion

what type of cadherins attract

same type

what type of cadherins repel

different types

cadherins produced by epithelial cells

E-cadherin

cadherins produced by nervous tissue

N-cadherins

what regulates strength of addhision

cadherin concentration

stronger cadherin concentration

more central tight location in embryo

weaker cadherin concentration

outer layer of embryo

how would these cells organize after being mixed together

B-cells would be in the center, C-cells would be the middle layer, and A-cells would be the outer layer

what can changes in cadherin expression drive

morphological events

how does cadherin expression change as a cell separates from one tissues and migrates to another

the cadherin expression gets weaker

epithelial-to-mesenchymal transition (EMT)

when cells that are originally attached to one another (as part of the epithelium) separate and migrate away

what happens when a tumor becomes metastatic

part of the tumor has undergone an inappropriate EMT

what cancers is the downregulation of cadherin expression linked to

breast, lung, and oral cancer