PI3-K/PTEN/Akt pathway.

When IGF (insulin-like growth factor) binds to IGFR (insulin-like growth factor receptor),
autophosphorylation (PO4 ) of IGFR occurs.
PI3-K (phosphati dylinositol 3-k inase) binds to IGFR-PO4 and catalyzes the conversion of PIP2
(phosphatidylinositol 3, 4 biphosphate) to PIP3 (phosphatidylinositol 3, 4, 5 triphosphate).
PTEN (phosphatase and tensin homolog) catalyzes the conversion of PIP 3 to PIP2. This
dephosphorylation is important because it inhibits the PI3-K/PTEN/Akt pathway.
PIP3 recruits and serves as a docking site for Akt kinase (t ransforming retrovirus isolated from the Ak
mouse strain) and PDK1 (phosphoinositide-dependent protein kinase).
Akt is phosphorylated by PDK1 and thereby activated.
Activated Akt dissociates from the cell membrane and can affect a myriad of substrates via its kinase
activity. Three possible pathways are shown.
Activated Akt phosphorylates BAD (bcl-xl/bcl-2-a ntagonist which stimulates cell death). Protein 14-3-3
binds toBAD-PO4 which sequesters BAD. Sequestered BAD inhibits cell death (or apoptosis).
Activated Akt activates mTOR kinase (mammalian t arget of r apamycin) through a series of steps (not
shown). Ac-tivated mTOR stimulates cell growth by increasing protein synthesis.
Activated Akt phosphorylates GSK3 (glycogen synthase kinase 3). GSK3 -PO4 is inactive. Inactive
GSK3 -PO
4 stimulates cell proliferation by increasing -catenin levels (the penultimate downstream mediator of the
WNT
signal pathway) and by increasing protein synthesis.



Mitogen-activated protein kinase (MAPK) pathway.

When FGF (fibroblast growth factor) binds to FGFR (fibroblast growth factor receptor),
autophosphorylation (PO4) of FGFR occurs.
This is recognized by SOS adaptor protein which activates GNRP (guanine nucleotide releasing factor).
GNRP (guanine nucleotide releasing factor) activates the G-protein RAS by transforming the bound
GDP to GTP (RAS-GDP Sactive RAS-GTP).
Active RAS-GTP attracts RAF kinase to the inner leaflet of the cell membrane and binds RAF kinase
causing a three-dimensional configurational change which activates RAF kinase.
Active RAF kinase phosphorylates MEK kinase.
Phosphorylated MEK kinase phosphorylates ERK kinase.
Phosphorylated ERK kinase enters the nucleus and phosphorylates the transcription factor ELK-1.
Phosphorylated ELK-1 complexes with SRF (serum response factor) leading to the transcription of
immediate early genes (called the early response), such as the MYC gene, FOS gene and JUN gene.
FOS and JUN mRNAs exit the nucleus and undergo translation to the FOS and JUN proteins.
FOS and JUN proteins enter the nucleus and dimerize to form the AP-1 transcription factor.
The AP-1 transcription factor leads to the transcription of late response genes (called the late response).
The late response genes include numerous growth factor genes
Ras-GTP is deactivated by GAP (GTPase activating protein) which convert it back to Ras-GDP. When
Ras is mutated it becomes less responsive to GAP.


SMAD (Sm a protein and Mad protein) pathway.

TGF B 1 is a cytokine which acts as a tumor suppressor in the early stages of oncogenesis through the
SMAD pathway.
When TGF Bbinds to the Type II TGF B receptor, the Type II TGF B receptor binds the Type I TGF B
receptor and phosphorylates it.
The phosphorylated Type I and Type II TGF B receptor complex phosphorylates the R-Smad protein
(receptor-regulated Smad protein).
The phosphorylated R-Smad protein binds to Co-Smad protein (common partner Smad AKA Smad 4).
The heterodimeric Smad complex enters the nucleus.
The Smad complex works with other transcription factors.
This leads to the transcription of various genes some of which trigger apoptosis.












JAK-STAT pathway

- Ligand binds a receptor (eg. Cytokine receptor) activating Janus kinase AKA as JAK (tyrosine
kinase) which autophosphorylates itself
- The STAT protein then binds to the phosphorylated protein where STAT proteins are
phosphorylated by JAK.
- Then one phosphorylated STAT protein binds to another phosphorylated STAT protein (dimerize)
and translocates into the nucleous where it binds DNA
- JAK inhibitors are used in psoriasis and RA
Ruxotilinib JAK1/JAK2 inhibitor
Tofacitinib JAK3 inhibitor



A. Red blood cells (Figure 1.7A) have integrins, called band 3 proteins, which are located in the
plasmalemma. The cytoskeleton of a red blood cell consists mainly of spectrin, actin, band
4.1 protein, and ankyrin.
1. Spectrin is a long, flexible protein (about 110 nm long), composed of an
-chain and a

-chain, that forms tetramers and provides a scaffold for structural reinforcement.
2. Actin attaches to binding sites on the spectrin tetramers and holds them together, thus
aiding in the formation of a hexagonal spectrin latticework.
3. Band 4.1 protein binds to and stabilizes spectrinactin complexes.
4. Ankyrin is linked to both band 3 proteins and spectrin tetramers, thus attaching the
spectrinactin complex to transmembrane proteins.
B. The cytoskeleton of nonerythroid cells (Figure 1.7B) consists of the following major
components:
1. Actin (and perhaps fodrin), which serves as a nonerythroid spectrin.
2. -Actinin, which cross-links actin filaments to form a meshwork.
3. Vinculin, which binds to

-actinin and to another protein, called talin, which, in turn, attaches to the integrin in the plasma
membrane.



8. Coated vesicles are characterized by a visible cytoplasmic surface coat.
a. Clathrin-coated vesicles (Figure 3.6)
(1) Structure. These vesicles are coated with clathrin, which consists of three large and
three small polypeptide chains that form a triskelion (three-legged structure).
Thirty-six clathrin triskelions associate to form a polyhedral cage-like lattice
around the vesicle. Proteins called adaptins are also part of clathrin-coated vesicles.
They recognize and recruit the clathrin coat, capture cargo receptors containing
specific molecules, and help to establish the vesicle curvature. A guanosine
triphosphate (GTP)binding protein called dynamin forms a ring around the neck of a budding vesicle or
pit and aids in pinching it off the parent membrane
to form a free clathrin-coated vesicle

b. Coatomer-coated vesicles
(1) Structure. These vesicles have coats consisting of coatomer, which does not form a
cage-like lattice around vesicles. Coatomer is a large protein complex formed by
individual coat protein subunits called COPs. Assembly of coatomer depends on
the protein ADP-ribosylation factor (ARF), which binds GTP, becomes activated, and
recruits coatomer subunits. ARF also helps to select the cargo molecules.
(2) Function
(a) Coatomer-coated vesicles mediate the continuous constitutive protein transport
(default pathway; bulk flow) within the cell. Specific GTP-binding proteins
are present at each step of vesicle budding and fusion, and proteins called
SNARES ensure that the vesicle docks and fuses only with its correct target
membrane. Coated vesicle SNARES (v-SNARES) recognize and bind to complementary
target SNARES (t-SNARES) to deliver not only cargo molecules but
also membrane to the target compartment (Figure 3.7).
(b) Coatomer-coated vesicles transport proteins from the RER to the VTC to the
Golgi apparatus, from one Golgi cisterna to another, and from the TGN to the
plasma membrane.
(i) COP-II transports molecules forward from the RER to the VTC to the cis
Golgi and across the cisternae to the TGN (anterograde transport).
(ii) COP-I facilitates retrograde transport (from the VTC or any Golgi cisternal
compartment or from the TGN) to the RER. It is still questionable whether
or not COP-I facilitates anterograde transport, but recent findings suggest
that they might move forward between Golgi regions to the TGN.

The interaction of v-SNARES with t-SNARES is essential for neurotransmitter
release, via exocytosis, at chemical synapses. At the presynaptic
nerve terminal, one of the t-SNARES is SNAP-25, a fusion protein. Botox (botulinum neurotoxin A)
cleaves SNAP-25 and prevents the synaptic vesicles from anchoring and releasing their neurotransmitter,
thus preventing neuromuscular transmission and contraction. This leads to a flaccid paralysis
of the postsynaptic muscle.

c. Caveolin-coated vesicles. These coated vesicles are less common and less well understood
than those of the previous two categories.
(1) Structure. Caveolae are invaginations of the plasma membrane in endothelial and
smooth muscle cells. They possess a distinct coat formed by the protein caveolin.
(2) Function. Caveolae have been associated with cell signaling and a variety of transport
processes, such as transcytosis and endocytosis.