Cell-Cell Communication

Phosphorylation (in terms of protein regulation)

* Reversible
* Post-translational modification
* Causes conformational change in proteins that can either activate or inactive the protein’s function

Cyclin-Cdks

* Heterodimers (cyclin + Cdk)
* Regulate cell cycle
* Cyclin concentration changes, Cdk is present at constant levels throughout cell cycle

How is Cdk activated

By binding to a cyclin

What ensures that the cell cycle is uni-directional?

When cyclin-Cdks have successfully done their job for their phase of the cycle, cyclin is degraded to turn of MPF

General effect of a signal

Change in gene expression or other cell behavior

Describe characteristics of the signals cells emit/receive to communicate

* Small
* Soluble
* Protein or non-protein

Autocrine signaling

Same cell emits and receives signal (self-signaling)

Paracrine signaling

* Signal diffuses only microns away to neighboring cell
* Many paracrine signals are peptide growth factors

Juxtacrine signaling

AKA contact-dependent signaling

Cells must be immediate neighbors because the signaling molecule is attached to the signaling cell

Endocrine signaling

Endocrines signals diffuse over long distances via circulatory system

Intercellular signals are received by cells through protein ________

Receptors

What are the 2 types of signaling receptors?

1. Intracellular receptors
2. Cell-surface receptors

What type of signals bind to intracellular receptors?

Lipid-soluble signals (steroid hormones) that diffuse directly across the membrane

What type of signals bind to cell-surface receptors?

Lipid insoluble signals (peptide hormones)

To respond to a signal, a cell must express the ________ for that signal

Receptor

How do lipid soluble signals exert their effects?

* Induce a conformational change in the intracellular receptor
* The receptor itself brings about the change in cell behavior

Steps in signal transduction pathway

1. Receptor activation
2. Signal transduction
3. Response
4. Termination

Receptor activation

Ligand binds to a receptor which is then activated by a conformational change

Signal transduction

Conversion of the extracellular signal to an intracellular signal

Purpose of termination of signal transduction pathway

So that new signals can be received

Ligand-gated ion channels

* Receptors that alter the flow of ions across the plasma membrane
* When a signaling molecule binds to the extracellular ligand-binding site of the channel protein, the channel’s pore opens and allows ions to flow in or out

Signal amplification

* Allows a cell to be sensitive to incredibly small concentrations of signaling molecules
* One ligand induces many copies of an intracellular signal
* This may be accomplished by the activation of an enzyme because enzymes can catalyze reactions repeatedly without being used up

G protein-coupled receptors (GPCRs)

* Associated with G proteins, which bind to GTP or GDP
* Ligand binding to GPCR causes GPCR to undergo conformational change

GPCR activated state

* In the activated state, the GPCR induces the G protein to replace (NOT phosphorylate) GDP with GTP
* A G protein is active in the **GTP-bound state**

The G protein is always associated with the membrane by (1) ___________ which means that G proteins are an example of (2) __________________

1. Lipid anchors
2. Peripheral membrane proteins

GTPases: almost always, a protein is active in the (1) ________- bound state and inactive in the (2) _______ - bound state, meaning that the energy of (3) ____________ is used by the cell to accomplish regulation of cell behavior

1. GTP
2. GDP
3. GTP hydrolysis

Characteristics of second messengers

* Small molecule
* Concentration constantly increases or decreases in response to an extracellular signal
* Diffuses rapidly and helps relay the signal to other signaling proteins in the cell

Adenylyl cyclase (function, how is it activated)

* Catalyzes the conversion of ATP into the second messenger cyclic AMP (cAMP)
* Adenylyl cyclase is activated by a G protein

Amplification of signaling through GPCRs

1. Each ligand-bound receptor activates multiple G proteins
2. Each adenylyl cyclase produces large amounts of cAMP
3. Each active protein kinase A phosphorylates multiple copies of its protein targets

Termination of GPCR signaling (4 factors)

1. **Ligand goes away** (based on affinity and extracellular concentration)
2. **G protein hydrolyzes GTP to GDP**
3. **Phosphodiesterases** cut the cyclic bond in cAMP (yielding AMP)
4. **Phosphatases** remove phosphates from the activated target proteins

What is the amount of time a signaling molecule remains bound to its receptor dependent on?

Its **binding affinity** for the signaling molecule

What are the two changes within a cell GPCRs usually cause that allow them to exert their effects?

1. Changing the intracellular concentration of a second messenger or
2. By altering the activity of ion channels, changing the membrane potential

How are receptor tyrosine kinases (RTKs) activated?

Ligand-induced dimerization

Kinase domain on RTK

Portion of protein that can remove a phosphate from an ATP and transfer it to something else

RTKs: trans-phosphorylation

Each member of the receptor pair (post-dimerization) attaches phosphate groups to the other member

RTKs: recruitment and activation of cytoplasmic signaling proteins

The attached phosphate groups (phosphotyrosines) provide binding sites for intracellular signaling proteins

Many RTKs generate an intracellular response through ___, which:

Ras, which activates the MAP kinase signaling pathway

Describe the activation of Ras

Signaling proteins bridge the receptor to the Ras GTPase which induces Ras to exchange GDP to GTP, rendering it active

What does Ras do once activated?

Activates the upstream member of kinase cascade, leading the phosphorylation of target proteins, which brings about a change in cell behavior

Why do responses to a signal vary according to cell type?

Because each cell only expresses a subset of receptors

Describe the relative speed of signaling that causes:


1. Altered protein function
2. Altered protein synthesis

1. Altered protein function = FAST (seconds to minutes)
2. Altered protein synthesis = SLOW (minutes to hours)

Signal integration

Multiple variables determine the outcome (which *combination* of signals a cell is receiving at once determines its behavior)