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Cell Signaling in Space and Time

:
Where Proteins Come Together and
When They’re Apart

Cells typically receive chemical signals via
signaling molecules and integrate the
information they receive. receptors which are
transmembrane proteins specifically bind the
signaling molecule and initiate a signal
transmission through a sequence of molecular
switches to the cell interior.
for all of these signaling pathways, information
is conveyed either through protein–protein
interactions or it is transmitted by diffusible
elements usually referred to as second
messengers

Requirements for Processing of
information
Cells have developed four regulatory mechanisms to ensure
all the elements needed for processing the information come
together at the right time and right place.
•Signal dependent formation of protein complexes
•Processing of signals through preassembled protein
complexes
•Enzyme regulation by subcellular localization
•Temporal control of signaling pathway

• Protein complex formation requires Post
translational modifications such as
phosphorylation, phosphoinositides,
ubiquitination, and acetylation,… which
allows communication between cells.

SH2 domain
• SRC Homology 2 (SH2) domain : sequence-specific
phosphotyrosine-binding module
• Discovered in P130Gag-Fps oncoprotein
• Contains 100 amino acids which bind to pY
• Adapter proteins contain several domains such as the
SH2 and SH3 domains within their structure, thus
allowing interactions with other specific proteins.
SH2 domains bind to receptor tyrosine kinase and
SH3 domain recognize proline-rich sequences

• SH2 domain interactions with SH3 domain can
lead to Kinase inactivation. SH2-SH3 unit
block the activity of Abl, Src, Lyn, Fyn.
• They act by stabilizing the enzyme inactive
conformation and suppressing its activity.
• SH2 domain have the ability to discriminate
between adjacent residues and recognize
different phosphorylated sites.

NcK adapter protein
• NcK adapter protein consists of one SH2
domain and three SH3 domains. It links
receptor and nonreceptor tyrosine kinases to
actin cytoskeleton reorganizing proteins, they
are involved in cell movements and axon
guidance.
• Stabilizing interactions between the SH2 and
the kinase domains have also been observed in
FES SH2 functional unit

Grb2 adaptor protein
• Grb2 adaptor protein and effector proteins
such as phosphatidylinositol 3-kinase (PI3K)
or phospholipase–Cg (PLC-g) are recruited
when receptor tyrosine kinase becomes autophoshphorylated which causes progression of
cancer cells.

Histone Ubiquitination
• post-transcriptional modification which plays an essential
role in regulation of all DNA related processes
• Poly ubiquitination: 76 amino acid polypeptide attached to
histone lysines and signal proteins for degredation via 26S
proteosome
• Ubiquitin-binding domains (UBDs) are a collection of
modular protein domains that non-covalently bind to
ubiquitin. Because these bindings are readily reversible
UBD motifs interpret and transmit information and control
various cellular events such as endosomal sorting, vesicular
trafficking, …

Acetylation
• Acetylation of lysine residue is highly dynamic and is controlled
by two families of enzymes:
1) HATs: Histone acetyl transferase- utilize
acetyl- CoA as a cofactor. Catalyze transfer of an
acetyl group
to the e-amino group of lysine side chains. Ubiquitination of the
same side chain can be prohibited by lysine acetylation.
For example when the cell DNA is damaged, tumor suppressor
protein P53 is stabilized by acetylation results in protection of P53
from degradation from ubiquitin- proteosome.
2) HDACs: Histone deacetylases- have relatively low substrate
specificity. A single enzyme can de-acetylate multiple sites within
histones.

Protein Complexes
Signal Integration

How is this
achieved?
• Think of the overall
machinery as an
automated car
wash.
• Car represents
substrate
• The car needs to
follow a series of
steps in a
predetermined
sequence in order
to be washed
properly.

Signal processing through protein
complexes
• Linear flow of signaling information
• Easier to manage protein-substrate
interactions
• Improves fidelity of cell signal
• Overall efficiency of a signal pathway
increases

Efficiency & Fidelity
• By clustering all the instruments
required for
substrate
processing the process becomes
more efficient and faithful.
• Members of the protein complex will only
process the previous substrate.
– Ex: on a 3 member protein complex 2
will only process the product of 1, and
three the product of 2.

Some examples:
• MAPKs (mitogen-activated protein
kinases)
• JNKs (Jun N-terminal Kinase)

MAP-Kinase (mitogenactivated protein)
Signaling
• Linear flowModule
of signals

Growth Factor Stimulates
RTKs (receptor tyrosine
kinases)

Starts signal

Ras (GTP-binding protein)
forms complex with SOS
and Grb2 protein to form
the active form of Ras
This allows MAP KKK to
phosphorylate MEK1/2 (MAP
KK) and then MEK1/2
phosphorylates ERK1/2
(MAP K)
ERK1/2 is then free to
phosphorylate different
combinations of proteins
and begin transcriptional
regulation
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Temporal Control of Signaling
Pathways
• Changes in the composition or the
amount of enzyme complexes over
time modulate the cellular event
– Ex: phosphorylation , degradation by
ubiquitation or the translocation of
signaling components.

Nuclear factor kB
• is transcription factor that regulates
expression of genes involved in
inflammation, apoptosis and
tumorigenesis
– IkB kinases complex  phosphorylation
 ubiquitination  degradation 
translocation to the nucleus

Hypoxia-inducible factor 1 α(HIF-1
α)
• Is induced in cardiomyocytes and
tumor in response to reduced
intracellular oxygen

– In the normoxic condition, the concerntration is
low beacause of its ubiquitin-mediated
proteosomal degradation.
– In the hypoxia, enzymatic activity of PHD halt
the destruction of the HIF-1α , and E3 ligase
ubiquitinates and degrades the HIF-1 α.
 The degraded HIF-1 α is translocated to the
nucleus and combine with the HIF-1β to form a
heterodimetric complex to initiate the
transcription of proangiogenic, metabolic, and
antiapoptotic genes that promote cell survivial