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Tyr-X-X-M sequence: are phosphorylated by the receptor tyrosine kinase
Met
IRS phosphoinositide 3-kinase:
a lipid kinase, 110 kd catalytic subunit and 85 kd regulatory subunit
containing a SH2 domain: Src homology 2, recognize the
phosphotyrosine residues in the IRS, via two Arg residues that are
conserved in all SH2 domain
phosphoinositide 3-kinase PIP3
PIP3-dependent protein kinase
Akt: a kind of protein kinase, is not membrane anchored
Glucose transporters (GLUT4)
Stimulate glycogen synthesis
Membrane-anchor molecules
Amplicification/ termination
phosphatase phosphatase
phosphatase
Type 3: EGF (epidermal growth factor) signaling
stimulate the growth of epidermal and epithelial cells
a receptor tyrosine kinase, a 6 kd polypeptide
3 intrachain disulfide bonds
EGF receptor structure
EGF receptor:
is a dimer of two identical units, but exist as monomers until EGF
ligands bind to them
each monomer binds a EGF molecule in its extracellular domain
each EGF molecule lies far away from the dimer interface
a dimerization arm from each monomer that reaches out and inserts
into a binding pocket on the other monomer
If EGF is absent?
binds to a part of within the same monomer
Once EGF present,
Change into a active conformation
A constitutive active form ?
Her 2 receptor, 50 % identical in aa sequence
with the EGF receptor and has the same domain
structure
Her 2 is overexpressed in some cancers
EGF phosphorylation:
also like insulin receptor, cross-phosphorylation of one unit by another unit
within a dimer, but
its carboxyl - terminal tail containing tyrosine rich (5 residues)
the kinase itself is an active conformation without phosphorylation
Dimerization C-terminal region on one receptor into the active site
of its partner’s kinase
Grb-2: an adaptor protein
SH2 domain phosphotyrosine residues of receptor
SH3 domain proline-rich region of Sos
Sos: a guanine-nucleotide-exchange factor (GEF)
Ras: small G proteins, small GTPase
localized to the inner surface of plasmamembrane
two
phosphatase
GTPase-activating proteins (GAPs)
G proteins vs. small G proteins(divergent evolution)
G proteins small G proteins
30-35 kd 20-25 kd
heterotrimer monomer (similar to G)
7TM dimerization
GTPase act. GTPase act. (low)
GTPase-activating proteins (GAPs):
facilitate GTP hydrolysis Sos + GAPs adjust small G cycle
ras mutation cancer
14.4 Many elements recur with variation
in different signal transduction pathways
Protein kinases are central
Second messengers
Specialized domains
pleckstrin homology domains: interact with lipids PIP3
SH2 domains: interact with the phosphorylated tyrosine residues
Some virus induced cancer– to understand the signal-transduction proteins and
pathwaysRous sarcoma virus: a retrovirus, a oncogenic RNA virusviral sarcoma (v-src): oncogene [A cancer-causing gene; any of several m
utant genes that cause cells to exhibit rapid, uncontrol proliferation.] cellular sarcoma (c-src): proto-oncogene, does not induce cell transformat
ion
a. SH2 bind to tyr-P of C-terminalb. The linker between SH2 and protein kinase is bounded by SH3 c-Src inactive
v-Src: 11 aa of C-terminal, lack Y residue
always active
Biology/chemical/physical factors
c-Src
19 aa
Ras: a small G protein or GTPase– localized to the inner surface of plasmamembrane
The small G proteins
Three 21-kd Ras proteins in mammalian cells
H-Ras: Harvey rat sarcoma
K-Ras: Kirsten rat sarcoma A loss of the ability to hydrolyze GTP
N-Ras: Neuroblastoma rat sarcoma continue on
Tumor-suppressor genes (contribute to cancer development):
to develop cancer only when both copies of the genes normally present in a cell
are deleted or otherwise damaged.
e.g., genes for some of the phosphatase
Monoclonal antibodies utilization:
inhibit the signal transduction in activated tumor formation
In some human epithelial cancers, such as breast, ovarian, and
colorectal cancers, overexpressed the epidermal-growth-factor receptor (EGFR)
Monoclonal Ab offend receptor
e.g., Cetuximab, target a receptor tyrosine kinase
Trastuzumab (Herceptin): inhibit Her2 overexpressed in breast cancers
Protein kinase inhibitor– a potential anticancer drugs
Chronic myologenous leukemia (CML)
chromosome defect:
the translocation between chromosome 9 and 22
(reciprocally)
Bcr-Abl fused protein:
overexpress kinase activity and is not regulated appropriately
STI-571: a specific Bcr-Abl kinase inhibitor
encode tyrosine kinase
To understanding the signal-transduction pathways is leading to conceptually new disease treatment.
Metabolism disease
Choleragen
a cholera toxin from Vibrio cholera (G -) two functional units: subunit B: bind to GM1 gangliosides of intestinal epithelium (p. 738) subunit A: enters the cell, catalyze the covalent modification of Gs
proteinGs + subunit A Gs-Arg-ADP-ribose
stabilize Gs-GTP form (perpetually stimulation)
activate adenylate cyclase
[cAMP] activate protein kinase A
open Cl- channel / inhibit Na+-H+ exchanger
NaCl and H2O loss
Treatment consists of rehydration with a glucose-electrolyte solution.
Pertussis toxin
is secreted by Bordetella pertussis
Gi + pertussis Gi-ADP-ribose
reduced Gi-GTP affinity
inhibit adenylate cyclase
[cAMP] close Ca2+ channels and open K+ channels
Altered G-protein activity caused diseases
(02)
96T
(191)
96T (192)
STAT5(signal transducers and activators of
transcription)–– a regulator of gene expression
–– is phosphorylated by JAK2
recirpocal interaction
(02)
97T
Which of the event is important for epidermal growth factor signaling?(A) ADP-ribosylation (B) Farnesylation (C) Mono-oxygenation (D) Peroxidation (E) Glycosylation (94, 台大 ) p. 284