Cell To Cell Signaling

Front 1

Cell surface vs. intracellular receptors
-location
-properities of signaling molecule
-types of molecules that bind to these receptor types

Back 1

cell surface receptors: on PM and respond to hydrophilic signal sequence on protein

Hormones and Membrane receptor binding: glycoproteins, amines (epinephrine and norephinephrine), polypeptides (less than 20 AA, Growth hormone), proteins (more than 20 AA), tyrosine derivitives

Intracellular receptor: located inside nucleus, small hydrophobic molecule carried to cell by a carrier protein and brought into cell

Hormones and intracellular receptor binding: extracellular ligands that do intracellular binding; steriods

Front 2

Secreted Ligands
-general mechanism
-3 types of signaling (endocrine, paracrine, and autocrine/examples)

Back 2

-Secreted molecules: released from signaling cell and travels in cytosol to cell surface receptor on target cell

1. Endocrine signaling: hormones secreted by endocrine cells and carried through circulation to distant target bodies

2. Paracrine signaling: molecules released by one cell act on neighboring target cells

3. Autocrine signaling: cells respond to their own produced signaling molecules (examples: prostiglanin signaling; T-cells make a GF in response to antigens that causes their own proliferation and amplifies the immune response)

Front 3

Membrane-Bound Ligands
-general mechanisms
-2 types of signaling

Back 3

PM-bound ligands: signaling molecule located on PM and signaling and target cells come in close contact so molecule can bind to its receptor on the target cell

Delta-notch= PM bound molecules require direct contact

2 Types:
1. ligand-receptor interaction: activates intracellular signaling molecules
2. Gap junctions: open junctions with direct connection; channel made of 6 connexin proteins to make a connaexon

Front 4

Same signaling molecule can induce different responses
-2 ways

Back 4

-dependent on the receptor expressed on the target cell OR on the internal machinery that the receptors bind to

1. difference in target receptor:
Ach receptor is different on skeletal muscle and heart muscle cells
-Ach binding causes contraction in skeletal muscle and relaxation in heart muscle, and can cause secretion in secretory cells

2. same receptor bound to the same ligand can cause different target cell responses b/c of differences in internal machinery that is bound to the intracellular part of the receptor

Front 5

Regulation of ligand concentration
-controlled by 2 ways

Back 5

ligand concentration controlled by
1. Rate of synthesis
2. Half-life or Turnover rate, also determines promptness of response

Front 6

Combitorial signaling and signaling amplification

Back 6

Combitorial signaling: integration of multiple signals to create a certain response
Example: Signals A B and C tell cell to survive. Addition of signals D and E tell cell to proliferate
-combination of all 5 signals= proliferation response

Amplification: 1 ligand binds to 1 receptor which yields 10^6 activated products
Example: PTH-PTH receptor activates Adenylyl cyclase, then cAMP, PK, enzyme phosphorylation, then products
-amplification occurs in each molecule as you go down the pathway
***NO signal amplification occurs without ENZYME ACTIVITY

Front 7

signaling pathways via membrane receptors
-ion channel
-receptor tyrosine kinase
-JAK/STAT
-GPCR
-what do they all have in common?

Back 7

1. Ion channel: "ligand gated ion channel"; on PM**; messanger binds to receptor and causes change in channel confirmation; results in change in membrane potential and/or cytosolic Ca2+ concentration which causes cell's response

2. Receptor Tyr Kinase: **Receptor has intrinsic kinase enzyme activity (difference from JAK/STAT) and docking protein that leads to cell's response

3. JAK/STAT: **JAK has kinase activity seperate from receptor; JAK binds to receptor and phosphorylates a protein that leads to a cell response

4. GPCR: receptor-ligand causes G protein to bind to and activate ion channel or enzyme (GPCR embedded in membrane); GPCR causes a change in membrane potential for ion channels OR generates second messangers which lead to cell's response (used in IP3/diacylglycerol pathway)

**All lead to downstream signal amplification b/c they involve enzyme activity

Front 8

Desensitization of target cells to signal
1. receptor sequestration
2. receptor down regulation
3. Receptor inactivation
4. inactivation of signaling protein
5. production of inhibitory protein

Back 8

1. receptor sequestration: signal binds to receptor and induces endocytosis; they go to the endosome. Signal molecule is removed from receptor and receptor is recycled to the membrane.

2. Receptor down regulation: signal binds to receptor and induces endocytosis; both get degraded in the lysosome. Long-term sensitization b/c cell has to make more receptor to be able to respond to ligand (takes 6 hrs)

3. Receptor inactivation: signal can bind to the receptor but nothing happens b/c the receptor is inhibited

4. inactivation of signaling protein: signal binds to receptor, but next protein in activation cascade is inhibited

5. Production of inhibitory protein: signal binds to receptor and an inhibitory protein blocks the signal transduction/activation of the next protein in the cascade

Front 9

Signal transduction and targeting disease: osteoporosis
-characteristics of osteoblasts
-integrated signaling during bone formation (what signaling pathways are influencing osteoblast maturation/differentiation)

Back 9

Osteoblasts build bone:
-precoursors in marrow and bone; derived from mesenchymal lineage (same cell lineage as myoblasts, fibroblasts, adipocytes, and chondrocytes)
-always found in clusters of cubodial cells along bone surface
-difficult to recognize b/c they don't have many specific markers

Integrated signaling during bone formation:
-Hormones, GF, and cytokines modulate osteoblast formation at all levels: they affect precoursor cells to be recruited to maturation pathway as presteoblasts, affect proliferation stage, and maturation stage/matrix synthesis
-formation rates modulated at precoursor level by effects on differentiating and mature osteoblasts, and osteocytes (mechanical regulator of bone cell function)

**all signaling pathways (intracellular, affect transcription) cross-talk and lead to matrix protein synthesis which leads to osteoblast differentiation

Front 10

Signal transduction and targeting disease: Cancer
-3 signaling pathways that when mutated can lead to cancer
-role of oncogenes in signal transduction, what do they code for?
-tumor suppressor genes: how tumor formation can occur
-phosphatases
-Drug therapies used to target signaling pathways

Back 10

**abnormal autocrine signaling often contributes to cancer

Mutations in 3 signaling pathways can lead to colon carcinoma:
-wnt pathway (APC and beta-catenin)
-receptor tyr kinase (rasK, B-raf)
-receptor Ser kinase (**tumor suppressor genes TbetaRII, Smad2, Smad4)

-onocagenes= proteins that regulate cell proliferation b/c they are involved in these GF-stimulated signal transduction pathways. Mutations in these oncogenes causes uninhibted cell proliferation

*Protein-tyrosine kinases: GF receptors which are encoded for by oncogenes, or are targeted by TF encoded for by oncogenes

Tumor suppressor genes:
RSK pathway: mutations in genes for this pathway lead to colon cancer

2 ways tumor formation occurs:
1. mutation in tumor suppressor gene that results in abnormal function
2. diminished expression of a normal suppressor protein
**PERMISSIVE for cell proliferation

-Phosphtases may function as tumor suppressors (like PTEN) b/c many proto-oncogenes are protein kinases

Drug therapies:
-Herceptin, Erbitux, STI-571, and Gefitinib target RTK signaling
-Retinoic acid targets steroid/nuclear receptor signaling