unit 7 - cell communication

5 modes of signal transduction

1. Paracrine

2. autocrine

3. juxtacrine

4. endocrine

5. synaptic

paracrine

• secrating cell relase signal into ECM

• sigal acts localy on nearby cells (cant diffuse long distances)

• site of rease = site of action

autocrine

• same as paracrine but cell is trageting its self

juxtacrine

• signal molecule raimins bound in the secreting cell

• traget cell recepotr makes contact with the secreating cell

endocrine

• siganl molecules is relased directally into the blood streams by endocrine cells

• sigal trvels to distant loaction and is picked up by all cells

synaptic

• electracal siganl converted to chemical signal

• electral signal along nerve traggers release of neurotransmitter

8 functions of ECM

1. Ancorage

2. Migration barrier

3. Migration tracks

4. Signal reservoir

5. low affinity co-receptor

6. signal presenter

7. functional fragments

8. biomechanical force

anchorage

1. Maintain cell polarity (the absorptive side is always faceing the right way)

2. Decrase metabliosm/ growth if not connected to ECM

migration barrier

1. Prevests cells from moveing in a direction that they are not supposed to

migration tracks

Guide cells in direction that they are supossed to go

signal reservoir

1. Prevents free diffusion of siganl molecules

2. Regulaes bioavalibility

3. Acts as a 'sink'

4. Don’t want growfactors just foalting around so resevoir will hold them intill needed

low affinity co-receptor

1. ECM binds singinaling molcules

2. Enhance/ facilitate binding to traget receptor

signal presentor

1. Present signal to target cell

2. Deterimes direction of signaling

3. Paritcupate in juxtacrine signaling

Functional fragments

1. Enzymes called MMPs = matrix metal proteinases

2. Chew up ECM creating signal molecules

biomechanical force

ECM componets allow to cells to detect and respond to stiffness of ECM--> cells can change their behavour in respose

Bone (connective tissue)

• Rigid, calcified ECM

• Few cells (holes in pic)

• Moslty matrix

cartlidge (connective tissue)

• More flexible ECM

• Moderate number of cells

• Mostly matrix

• Hydrated ECM (shock absorption)

loose areolar (connective tissue) fibroblast

• Mostly fibers

• Lots of cells

• Find benieth mosly cells in the body

collagens

• structural protiens in the ECM

• large family of ifbruos glycoprotiens found only in vertabrates

• most of the ECMs strength in its high tensile strength

• collagen is the most abundent protein in mammals

sythesis of collagen fibers

1. 3 of alpha chain form triple helix (procollagen, has loose ends)

   1. Procollagen is secreted from ER --> ECM

2. Enzyme procollagen peptidase trims ends, now called tropocollagen (mature collogen)

3. Tropocollagens self assemble in to fibrils

   1. Fibril is stabilized by covalent bonds and H-bonds

   2. Bonds due to hydroxylated amino acids (proline, lysine)

   3. Has a striated pattern

4. Collage fibrils assemble in to collogen fiber

2 main types of collagens

long, strong fibrils with uniform cross-striations

• type 1, 2, 3, 5, 11

ones that do not form long fibrils

• type 4

Elastins (structural protiens)

• no hydroxylysine, some hydroxyproline

• tropelastin made in ER, assenbled into elastic fibers in the ECM

• sheets and fibers that allow for streching

GAGs

• glycosaminoglycans (long unbranched polysaccharides)

• hyaluronic acid are specialized GAGs

examples of GAGs

Hiparan - blood cloting

heparan sulfate - epithelium and endotherlium

dermatan sufate - skin

chondroitin sufate - cartilage

hyaluronic acid - everywhere

keratan sufate - carona of eye, brain

Hyaluronic acid

unique among GAGs

• made by enzyme in PM

• found free in ECM

• serves as backbone of large proteoglycan complexes

features of Hyaluronic Acid

1. very hygroscopic (atracts lots of H2O)

2. Viscoelastic

3. Very biocompatable

4. non-immunogenic

5. no toxic breakdown products

Laminins (adhesive glycoprotiens)

• 3 chains held together by disulfide bonds (has coiled and globualar regions)

• Functional domains

  • Different ECM components

  • Binding to cells via integrins

• Very important for basal lamina formation*

  • Underlines epthirail, endotherial, muscle and fat cells

organoids

grow your own organ in culture

contains basal lamina (laminin, collagen), GAGs (heparan sulfate

found in prescription medicine, development, drug discovery

integrins (cell-ECM interactions)

• Large family of receptors

• Heterodimers

• Tend to cluster together(10-1000 time more in an area that other receptors)

Bind cytoplasmic components

• Alpha (18) and beta (8) subunits heald together by noncovalent interactions/bonds

• They need to be able to move around (not stuck together)

integrin Mechanism of action

inactive form = “legs together”

• noncovslent interactions

• globular head curved inwards

• low affinity confirmation

active form = “legs apart”

• low affinity binding couses conformational change in integrins and legs spearate

• integrin stritens and binds ligand with high affinity

functions of integrins

1. adhesion of cells to substream (ECM, cell culture dish)

   • focal adhesions

   • hemidesnosomes

2. signal transduction

   • outside-in (where the molecue tha tactivates the integrin orignates from)

   • inside-out

3. adhesion to other cells

   • leukocyte-binding integrins

focal adhesions

• Outside-in: integrin bonds to ECM ligand (cologen, fibronectin) --> initiates focal adhesion formation

• Globular heads bind ECM ligand --> causes confomational change in integrin transmitied to cytoplasmic side

First --> binding of Talin or vinculin to integrin

--> polymerization of actin mincrofilliments

• causes a cascade inside the cells, can also result in change in gene expression

hemidesmosomes

they are found in the tighest point of attachment between cell and ECM

• they are only in epithelal/ endothelial cells (non-migratory)

the imporance of cell adhesion to substratum

dieases like “ butterfly children” or bullous pemphigoid

signal transduction

outside-in, inside out

outside in

• ECM binding (collagen) actives intgrin which recruits cytosolic proteins like talin

• ex) focal adhesions

inside out

• cytosolic protein (talin) binding activates intgrins which binds ECM componets

• ex) platelet activation

steps for platlet activation (inside out)

1. Vascular injury

   1. Wall endothelium has been comprimised

2. Collogen from the basl lamlina is exposed to the bloodstream

3. Platelet adheasion

   1. Membrane receptors of the first few platlets bind to the exposed collogen

   2. "first responders"

4. Intracellular cascade inside the first platelets

5. Platelet activation - round 1

   1. Cascade activates intergrens of the first platelets

      1. Bindfibrinogen and other blood proteins

   2. Inside-out activation

6. Platelet activation - Round 2

   1. First platelets release other molecules (ie ADP) that activate the second round of platelets

      1. Express integrins

   2. Outside-in activation

7. Other platelets bind the same fibrinogens

   1. Platelet aggregation

   2. Formation of platelet plug