• SER -> Golgi -> membrane
• Even # of C
• OH -phosphodiester-Glycerol or sphingosine
• Unsaturated =

• Polar hydroxyl group & hydrophobic steroid ring
• Increases packing of phospholipids & slows lateral mobility

• Get sugar group in Golgi
• signaling for cell-cell and cell-matrix

• Loosely attached to either side of bilayer
• Can remove without disrupting bilayer
• Attached ionically to integral proteins to form constituents of cytoskeleton
• Attach ionically to polar head for signal transduction

• Specialized cholesterol-enriched microdomains
• Phospholipids are tightly packed in raft
• Role in endocytosis, cholesterol transport & signal transduction

Transmembrane proteins: glycophorins & protein 3 (Anion transport channel)

Peripheral membrane proteins: Bound to inner membrane leaflet.  Spectin, ankyrin, actin, protein 4.1

• Actin protofilaments stabilized by tropomyosin
• Each protofilament binds 6 spectrin tetramers (hexagonal array)
• Spectrin-F-Actin complex stabilized by protein 4.1 which binds ends of spectrin
• Spectrin attached to bilayer by peripheral proteins ankyrin & band 3

• Cell movement, form contractile rings in cell division
• Many G actin -> 1 F actin (requires ATP)
• G actin keeps adding @ 1 side, falling a other, think multi lead pencils.
• regulates firmness of cytosol

• Structural role in nuclear envelope & plasma membrane
• Made of fibrous proteins

• Globular protein tubulin
• hydrolysis of tubulin bound GTP needed for constant assembly/disassemble.
• shuttles organelles
• spindle formation in cell division

• Amplify signal using second messenger
• ligand binds -> protein changes shape and binds to/activates G protein
• α subunit of G proteins bind to GTP 
• GTP is converted to GDP by G protein inactivating signaling process.

• Signal via +P of tyrosine.

1. Signal molecule binds to receptor
2. 2 receptor molecules come together in the membrane forming a dimer
3. each tyrosine tail +P to other.
4. adapter proteins containing SH2/SH3 dock with tyrosine+P and are activated.

STATS

Signal Transducers & Activators of Transcription

• SH2 containing latent proteins

1. Bind to tyrosine+P
2. When docked, acted on by tyrosine kinase and become tyrosine phosphorylated
3. Tyrosine phosphorylated STAT dimers go to nucleus, bind to DNA, and activate transcription.

• Cell survival & growth

1. P13 kinase binds to Tyr+P
2. Activated P13 kinase +P to PIP2 -> PIP3
3. Bad is +P by AKT to promote cell survival

1. Insulin binds to receptor
2. Insulin receptor tyrosine kinase activity activated
3. Induces tyrosine phosphorylation of IRS
4. Activated IRS binds to & activates SH-2 proteins (RAS, STATs, PI-3)

Nuclear initiated: Steroid travels in plasma, then enters target cell.  Receptor in cytosol or nucleus.  Binding regulates gene transcription

Membrane initiated: Receptor found on membrane.

G1

S

G2

M

G1: Cellular genome is diploid, resting state, make enzymes for DNA synthesis.

S: "Synthesis" DNA is replicated

G2: Make cell parts to prep for division.

M: "Mitotic phase" Cell devide.

Cyclin-Cyclin Dependent Kinase (CDK)

• Cyclin & CDK regulate cell cycle
• Cyclins ↑ & (↓ Proteosomal pathway)
• Cyclin + CDK = CDK protein+P -> +P to target protein.

• Association of CDK with cyclin
• Stimulatory phosphorylation sites
• Inhibitory phosphorylation sites
• Binding of inhibitory proteins (CDK inhib)

CDK1

CDK2

CDK1: Activates @ transition G2 -> M.  Targets mitotic machinery

CDK2: Activated @ transition G1 -> S.  Targets enzymes for DNA synthesis

When the cell is close to restriction point:

1. Growth factors induce cyclin D-CDK4 through MAP-kinase cascade
2. Cyclin D-CDK4 hyperphosphorylates RB
3. Inhibited release of E2F/DP1 by RB
4. Activation of genes who's products are important for entry into S phase

• Halts cell cycle for DNA repair with P21(CIP)
• Halts cell cycle at G1
• If bad damage, induces apoptosis.

1. Cell shrinks due to cleavage of lamin & actin
2. Chromatin breaks down, DNA condensation
3. Cell shrinks, eaten by macrophages

Attract MØ by releasing phosphotidylserine

• Caries out execution of cell death
• Catalytic cystein and cleaves target at an aspartate
• Synthesized as a proenzyme
• When initiator capsase induced, cleaves effector capsases for expanding cascade.

Pro survival: BCL-2, BCL-XL

Pro death: BAX, BAD, BID, BAK

• ratio of survival : death decides cell fate.
• Apoptosis mediated by cytochrome C from mitochondria
• Pro-death have BH3 region to inhibit pro-life

• BCL-2 at Outer mitochondrial membrane bout to Apaf-1
• Anti-apoptotic BCL-2 family in mitochondria
• Pro-apoptotic BCL-2 in cytosol

1. Pro-apoptotic BCL-2 sense cell damage
2. Pro-apoptotic travel to mitochondria surface
3. interaction between pro and anti cause mitochondrial membrane to depolarize
4. cytochrome c released into cytosol
5. Cytochrome c + Apaf-1 + caspase 9 = apoptosome
6. Effector caspases activated

1. On cell surface TNF-α binds to TNF or FasL binds to Fas. 
2. caspase 8 is activated
3. apoptosis, then phagocytosis by MØ

• Activation causes Serine/Threonine protein phosphorylation

1. Bound by TGFβ or BMPs
2. Dimerize & phosphorylate SMADs
3. Complexes of SMADs bind DNA, promote transcription.

• Target is MAPK and their activator kinases
• MAPK is activated by GTPase
• pathway terminates at nucleus where activate transcription for growth & differentiation

• Special stretches of AA in proteins for recognition and binding. 
• SH2 recognize Tyrosine+P and allow them to bind to activated Tyrosine Kinase receptors. 
• SH3 binds proline rich proteins

• Function as switches.  On when GTP, off when GDP.
• Ras activates a serine/threonine phosphorylation cascade that activates MAP kinase
• MAP kinase moves to nucleus to +P to proteins for gene transcription
• Activate cyclins & CDK.

• Deregulated tyrosine kinase activity of BCR-ABL is a transforming event in leukemia
• STI571 blocks the +P of tyrosine kinase by occupying the ATP spot of the Kinase.

• Point mutations prevent Ras inactivation by GAP
• Due to environmental carcinogens

• Ras proteins relay signals from membrane to MAP kinase in the cytosol
• Receptors have inherent tyrosine kinase activity
• MAP kinases are phosphorylated on serine and threonine AA residues
• MAP kinase translocated into the nucleus to activate cell proliferation