LE1 - General signaling principles
Intracellular signaling pathways are so important for cell function, hence a lot of diseases can occur
when cell signaling fails such as breast cancer, inflammatory bowel disease, and coronary heart diseases.
Signaling also evolves as life evolves. In unicellular organisms like in prokaryotes and a majority of
single-cell eukaryotes, when a single cell is kept in an environment with an unlimited nutrient supply,
they become immortal. However, as these unicellular organisms become more complex, they become
mortal, meaning that they have a finite life span and sometimes sequential progression of different
forms of single cells like in the case of the malaria-causing Plasmodium.
Further evolution then led to the emergence of multicellular collaboration between cell types like in the
case of slime molds where during times of nutrient scarcity, some cells can sacrifice themselves from
being mobile to form a stalk, conserving energy for the organism to reproduce. This highlights that there
is a need for control and coordination in a cell which gives rise to cell signaling.
Oncogenes and protooncogenes
Most of the oncogenes were discovered in retroviruses which are then labeled as “tumor viruses”. Most
oncogenes code proteins that hijack signaling and change the way a cell perceives its exterior or interior
environment (can be both), or the way the signal passes through the cell.
Classes of oncogenes:
1. Class 1: coding for growth factors
2. Class 2: coding for receptors
3. Class 3: coding for intracellular signaling machineries
4. Class 4: coding for transcription factors
All of these oncogenes are mimicking and undermining the functions of their healthy counterparts,
called the protooncogenes.
Signal transduction
This process of signal transduction is
the process to transmit a signal by
converting it from one form to another
which can cause a singular or
multifactorial response. Signal
transduction and cell signaling is all
about changes or perturbation from a
steady state which is reproducible,
managed, and controlled. For signaling
to take place, there should be
coordination: control in space and
,control of time (where and when in a cell and for how long). Other factors also play a role such as
position, concentration, duration, and the sequence of events.
Stimulus
Stimuli are basically things/molecules that
can get recognized by a cell namely
hormones, neurotransmitters, growth
factors, cytokines, lipids, surfaces and other
cells, mechanical stress, etc. They all have
different properties in terms of their size,
radioactivity, solubility, volatility, and if they
need to undergo proteolytic processing.
Examples are summarized in the table on the
right.
Reception
Molecules that detect these ligands are called receptors which come in many forms and sizes:
- Ion channels: voltage and ligand, intracellular
- GPCRs photons to thrombin, resident and dissociating ligands, proteolysis
- Oligomerized: growth factors, insulin receptor, TCR, IFN receptor
- Intracellular: steroids, nuclear receptors, transcription factors
Receptors are highly sensitive, only through binding of small numbers of molecules per cell can already
induce a big effect. Furthermore, many receptors have similar structures. This variety gives off a
diversity in receptors and to their specific functions/effect.
G-protein coupled receptors (GPCRs)
GPCRs have the same domains: a highly
glycosylated extracellular loops, 7
transmembrane helices, and intracellular
loops. The glycosylation pattern makes the
extracellular loops more rigid, providing them
structural support for the “harsh”
extracellular conditions. However, similarity
in structure doesn't always mean they have
the same mechanisms.
Activating pathways → See MC2 - GPCRs & Protein Kinases
Activation of proteins most often occurs through phosphorylation, a process of chemically adding a
phosphate group to certain amino acids (AAs). Phosphate groups can be looked at as a big clump of
negative charge. There are 5 AAs that can be phosphorylated, serine, threonine, tyrosine (3 most often),
,histidine (unstable product), and aspartate (in prokaryotes). Serine, threonine, and tyrosine are the most
common ones as they have a hydroxyl group. The phosphorylation reaction is shown below:
R-OH + PO4H → R-PO4 + H2O
The phosphorylation pathway employs cascades of proteins that need to be assembled and then they
amplify a signal. In general, upon phosphorylation (and/or dephosphorylation) of a protein, there will be
recognition of the phosphorylated site, leading to protein-protein interactions that can activate 2-state
G-protein switches. Kinases are enzymes responsible for phosphorylation while phosphatases are
responsible for dephosphorylation.
Switching on-and-off → See MC2 - GPCRs & Protein Kinases
The regulation of switching on and off is mediated mainly by either GTP or GDP. Proteins bound to GTP
are activated while GDP-bound ones mean they are inactivated. This exchange is mediated by GEF
(adding GTP) and GAP (adding GDP). These two forms are interconvertible, leading to a “toggle switch”
like system.
Mosaic proteins, domains, and fidelity → See LE2 - Protein domains and mosaic signaling architectures
A complex protein structure can be made out of multiple simpler parts called signaling domains. These
are discrete protein structural units which mediated specific molecular interactions within cells:
- C1 domains: bind to diacylglycerols (lipid metabolite) and tumor promoting mimics
- C2 domains: bind to phosphatidylserine and Ca2+
- SH2 domains: bind to p-tyrosine in peptides with specific consensus sequences
- SH3 domains: bind to polyproline containing helices (>3) with unusual geometry (very high
turning angle single the proline side chain is very rigid)
Signal integration and fail safe
Most of the time, only one signaling
domain is the “business end” where the
function of the whole protein is exerted
(e.g. kinase domains). The other domains
are there more for controlling and
assisting the function of the business
end. These controlling mechanisms allow
specific time and placement of the
activation of the protein.
Enforcing fidelity → See MC2 - GPCRs &
Protein Kinases
To ensure the specificity in the cell signaling, there are consensus sequences that guide the binding of
the kinases and downstream proteins such that the right amount of signaling is being induced to exert
the right amount of effect.
, Conservation and evolution
The general sequences of proteins are conserved through evolution which also implies the conservation
of structure. For example, kinases have the same structural backbone and the shape of the catalytic
subunit. Most of the AAs are for scaffolding which ensures that the active site where ATP and phosphate
group goes is protected. Not only the structure of the proteins are conserved, but the general pathway
and the elements playing in them are also highly conserved.
Different proteins have different interactions and different numbers of interactions. Some interact with
only one/two others in linear interactions. Others can interact with many different proteins, resulting in
a complex network of interactions that cannot be separated.
