How Signaling in biology points to design

How Signaling in biology points to design

https://reasonandscience.catsboard.com/t2745-how-signaling-in-biology-points-to-design

If I had to mention ONE word which refutes evolution by mutations and natural selection to explain biological development, body architecture, biodiversity, adaptation, regulation,  governing, controlling, recruiting, interpretation, recognition, orchestrating, elaborating strategies, guiding it would be: SIGNALING.

Eukaryotic cells use signal-transduction networks to respond in specific ways to external signals from their environment. Several signal transduction pathways are composed of multi-step chemical reactions. 3 Signal transduction is the process of routing information inside cells when receiving stimuli from their environment that modulate the behaviour and function. In such biological processes, the receptors, after receiving the corresponding signals, activate a number of biomolecules which eventually transduce the signal to the nucleus.  Signal transduction is a critical step in inter- and intra-cellular communication 4 The specificity of cellular responses to receptor stimulation is encoded by the spatial and temporal dynamics of downstream signalling networks. Temporal dynamics are coupled to spatial gradients of signalling activities, which guide pivotal intracellular processes and tightly regulate signal propagation across a cell. 5

Cells respond to external cues using a limited number of signalling pathways that are activated by plasma membrane receptors, such as G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). These pathways do not simply transmit, but they also process, encode and integrate internal and external signals.  It has become apparent that distinct spatiotemporal activation profiles of the same repertoire of signalling proteins result in different gene-expression patterns and diverse physiological responses. These observations indicate that pivotal cellular decisions, such as cytoskeletal reorganization, cell-cycle checkpoints and cell death (apoptosis), depend on the precise temporal control and relative spatial distribution of activated signal transducers. 

RTK-mediated signalling pathways have been in the limelight of scientific interest owing to their central role in the regulation of embryogenesis, cell survival, motility, proliferation, differentiation, glucose metabolism and apoptosis. Malfunction of RTK signalling is a leading cause of important human diseases that range from developmental defects to cancer, chronic inflammatory syndromes and diabetes. 

To understand the major trends in animal diversity and if the various kinds of morphology are due to evolution, we must first understand how animal form is generated. Above demonstrates that regulation of embryogenesis, cell survival, motility, proliferation, differentiation, glucose metabolism and apoptosis is due to  RTK-mediated signalling pathways, which play a central role in these processes, and as such, animal diversity and if the various kinds of morphology in the animal kingdoms. 

Upon stimulation, RTKs undergo dimerization  (for example, the epidermal growth factor receptor (EGFR)) a or allosteric transitions (insulin receptor) that result in the activation of the intrinsic tyrosine kinase activity. Subsequent phosphorylation of multiple tyrosine residues on the receptor transmits a biochemical signal to numerous cytoplasmic proteins, thereby triggering their mobilization to the cell surface4,10. The resulting cellular responses occur through complex biochemical circuits of protein-protein interactions and covalent-modification cascades.

What is signalling?
Cells must be able to respond rapidly and precisely not only to changes in their external environment but also to developmental and differentiation cues to determine when to divide, die, or acquire a particular cell fate. Signal transduction pathways are responsible for the integration and interpretation of most of such signals into specific transcriptional states. 1 Those states are achieved by the modulation of chromatin structure that activates or represses transcription at particular loci.

Post-translational modifications (PTMs) of histones provide a fine-tuned mechanism for regulating chromatin structure and dynamics. PTMs can alter direct interactions between histones and DNA and serve as docking sites for protein effectors, or readers, of these PTMs. Binding of the readers recruits or stabilizes various components of the nuclear signalling machinery at specific genomic sites, mediating fundamental DNA-templated processes, including gene transcription and DNA recombination, replication and repair 2

The is crosstalk between signal transduction and its consequent changes in chromatin structure and, therefore, gene expression. There is a relationship between chromatin-associated proteins and important signal transduction pathways during critical processes like development, differentiation, and disease. There is a great diversity of epigenetic mechanisms that have unexpected interactions with signaling pathways to establish transcriptional programs.

Secular science is FULL of evidence of intelligent design and the requirement of intelligent setup, but suppresses this obvious fact,  by not pointing it out.  

Following, an example:

Signals to and within the cell are integrated at many levels to facilitate a meaningful outcome. 6
https://www.nature.com/articles/nsmb0610-641

In other words, meaningful means: purposeful, intelligible, suggestive.

How could natural, non-intelligent, non-conscient chemical reactions evolve into producing signalling molecules and proteins, carrying meaning, and signals, that inform receptors to perform a precise, specific action? - Not forgetting, that there has to be a common agreement of the signal transmitter, and the receptor, of what the signal means?

More goes on than just the linear, sequential flow of information. Glycogen synthase kinase 3, for example, operates in multiple signal-transduction pathways.



This network of pathways permits the cell to respond in a coordinated fashion to instructions sent from the environment. Cells use a network with hubs, where multiple factors are located, and these hubs are an ideal venue for coordinating a response.

A cell ’ s response to its environment is often determined by signalling through the actions of enzyme cascades. The ability to organize these enzymes into multiprotein complexes allows for a high degree of fidelity, efficiency and spatial precision in signalling responses. 7  Control of cell signalling events occurs at many levels. Classically, regulation of catalysis occurs via interactions with metabolites, cofactors or chemical messengers that allosterically modulate enzyme activity. Additionally, the post-translational modification of enzymes and effector proteins alters the binding properties and activity of these macromolecules. Together, these modifications act to adjust the flow of information through signal-transduction cascades.

So, on top of the signalling cascade, there is a second layer of information, which controls the signalling events, enzyme modification and effector proteins b. 

Signalling generated by membrane proteins on the surface of Cell membranes points to design

Example: Cell division in bacteria
Cell division is a key step in the life of a bacterium. This process is carefully controlled and regulated so that the cellular machinery is equally partitioned into two daughter cells of equal size. 18 Most bacteria divide quite precisely and their daughter cells are often the same size.

Bacterial cell division or cytokinesis is the process in which a bacterial cell is split into two progeny cells, each with a copy of the chromosome.  In most bacteria this process in initiated by the formation of the Z ring, a dynamic structure consisting of polymers of FtsZ, a tublin family member. The Z ring recruits additional division proteins to form the septal ring, also called the divisome, which leads to the synthesis of the septum separating the progeny cells. Spatial regulation of Z‐ring formation occurs primarily through negative regulators of FtsZ assembly that are positioned within the cell. The Z ring forms where the concentration of these negative regulators is at a minimum. A variety of regulators and mechanisms for positioning them have been identified in different bacteria. 13

Rod-shaped bacteria that divide by binary fission, such as Escherichia coli, often mark their cell division sites at their cell midpoint so that daughter cells are roughly equivalent in size and shape. 14 So how does E. coli know where its middle is? Its cell poles are defined by the previous cell division, but, because E. coli grows by incorporating new cell wall and membrane uniformly along its length, the future cell division site at mid-cell is newly made and has no known pre-existing markers.

My comment: Cell division is life-essential. It had to be fully implemented when life began. But the mindless matter has no goals. Neither to become alive nor to perpetuate it. Cell division at the right place IMHO is life-essential. Bacterias have no knowledge. They had to be pre-programmed to divide in the middle. The "know-how" had to come from the implementer of the mechanism.  

One way to select the new mid-cell site would be to measure the distance from the two opposing cell poles, using a system that could recognize markers at those poles and define the spot furthest from both markers. This would require that both polar markers act negatively on cell division at equivalent intensities. The result would be a concentration gradient, with the lowest concentration of the negative regulator at the cell midpoint, the greatest distance from both cell poles. It turns out that E. coli and some other rod-shaped bacteria select their cell midpoint using such a negatively acting morphogen gradient, set up by the Min system.

In the bacterium Escherichia coli, the Min proteins oscillate between the cell poles to select the cell center as division site. This dynamic pattern has been proposed to arise by self-organization of these proteins, and several models have suggested a reaction-diffusion type mechanism, observed in a number of systems 8    Min proteins are crucial for accurate cell division and undergo spatiotemporal oscillations. They spontaneously organize into propagating wave patterns on supported membrane surfaces in the presence of ATP. The formation and maintenance of these patterns, which extend for hundreds of micrometres, require adenosine 5′-triphosphate (ATP), and they persist for hours.  Although the emergent behaviour is complex, the system can be quantitatively understood in terms of a reaction-diffusion model for membrane-surface inter­actions.  The oscillations of the Min system in Escherichia coli are a strong candidate for a reaction-diffusion system in vivo. This system consists of the proteins MinC, MinD, and MinE which oscillate between the poles of the rod-shaped bacterium and thereby select the cell center as the site for division septum formation. The Min proteins are crucial for accurate cell division. Mutants lacking the Min system are prone to divide asymmetrically, which gives rise to DNAfree minicells. MinD is an adenosine triphosphatase (ATPase) that dimerizes in the presence of adenosine 5′-triphosphate (ATP) and binds to the lipid membrane via amphipathic helices. 

The Min System is a mechanism composed of three proteins MinC, MinD, and MinE used by E. coli as a means of properly localizing the septum prior to cell division.


Model for MinD binding to the membrane. 
In this model MinD binds ATP leading to dimerization. This event activates the C-terminal amphipathic helix to interact with the membrane. Upon binding to the membrane hydrophobic residues from this amphipathic helix are inserted into the bilayer making the complex resistant to high ionic strength. 9

In the cell, MinD assembles on the cytoplasmic membrane covering roughly half of the cell. MinE binds to membrane-bound MinD and induces ATP hydrolysis by MinD.   Subsequently, both proteins detach from the membrane, and MinD reassembles in the opposite half of the cell. MinD and MinE regulate MinC activity by modulating its cellular location in a unique fashion. MinD recruits MinC to the membrane, and MinE induces MinC/MinD to oscillate rapidly between the membrane of opposite cell halves.  MinE stimulates the removal of MinD from the membrane in a wave-like fashion.  These waves run from a mid-cell position towards the poles in an alternating sequence such that the time-averaged concentration of division inhibitor is lowest at mid-cell. 10 Each component participates in generating a dynamic oscillation of FtsZ protein inhibition between the two bacterial poles to precisely specify the mid-zone of the cell, allowing the cell to accurately divide in two. This system is known to function in conjunction with a second negative regulatory system, the nucleoid occlusion system (NO), to ensure proper spatial and temporal regulation of chromosomal segregation and division. 11

So two separate, individual systems work as a team to perform the task. Is that not an irreducibly complex - / interdependent system, where one alone has no function? Had there not to be a planned endgoal beforehand, and complex problem-solving intelligence and mental input to program the function, to achieve the purpose of cell division, btw. essential for the perpetuation of life?



The MinCDE system.
MinD-ATP binds to a cell pole, also binds MinC, which prevents the formation of FtsZ polymers. The MinE ring causes hydrolysis of MinD’s bound ATP, turning it into ADP and releasing the complex from the membrane. The system oscillates as each pole builds up a concentration of inhibitor that is periodically dismantled. 12

The Min proteins prevent the FtsZ ring from being placed anywhere but near the mid cell and are hypothesized to be involved in a spatial regulatory mechanism that links size increases prior to cell division to FtsZ polymerization in the middle of the cell.

The MinCDE system.
MinD-ATP binds to a cell pole, also binds MinC, which prevents the formation of FtsZ polymers. The MinE ring causes hydrolysis of MinD’s bound ATP, turning it into ADP and releasing the complex from the membrane. The system oscillates as each pole builds up a concentration of inhibitor that is periodically dismantled.

Centering the Z-Ring
One model of Z-ring formation permits its formation only after a certain spatial signal that tells the cell that it is big enough to divide. The MinCDE system prevents FtsZ polymerization near certain parts of the plasma membrane. MinD localizes to the membrane only at cell poles and contains an ATPase and an ATP-binding domain. MinD is only able to bind to the membrane when in its ATP-bound conformation. Once anchored, the protein polymerizes, resulting in clusters of MinD. These clusters bind and then activate another protein called MinC, which has activity only when bound by MinD. MinC serves as a FtsZ inhibitor that prevents FtsZ polymerization. The high concentration of a FtsZ polymerization inhibitor at the poles prevents FtsZ from initiating division at anywhere but the mid-cell. By inhibiting FtsZ assembly at the cell poles, the Min system restricts the formation of the division septum to the cell-center.

How would and could non-directed, unguided, non-intelligent mechanisms arrive at such an elaborated mechanism, where an interplay of various different parts of the system are directed to a achieve a specific outcome, namely cell division, essential for the perpetuation of bacterial life on earth? It is an all or nothing business. Either all players are there, doing their assigned job, or cells do not divide.  

MinE is involved in preventing the formation of MinCD complexes in the middle of the cell. MinE forms a ring near each cell pole. This ring is not like the Z-ring. Instead, it catalyzes the release of MinD from the membrane by activating MinD’s ATPase. This hydrolyzes the MinD’s bound ATP, preventing it from anchoring itself to the membrane.

MinE prevents the MinD/C complex from forming in the center but allows it to stay at the poles. Once the MinD/C complex is released, MinC becomes inactivated. This prevents MinC from deactivating FtsZ. As a consequence, this activity imparts regional specificity to Min localization. Thus, FtsZ can form only in the center, where the concentration of the inhibitor MinC is minimal. Mutations that prevent the formation of MinE rings result in the MinCD zone extending well beyond the polar zones, preventing FtsZ to polymerize and to perform cell division. MinD requires a nucleotide exchange step to re-bind to ATP so that it can re-associate with the membrane after MinE release. The time-lapse results in a periodicity of Min association that may yield clues to a temporal signal linked to a spatial signal. In vivo observations show that the oscillation of Min proteins between cell poles occurs approximately every 50 seconds. 

In bacterias, there are various varying systems, which faithfully localize the Z ring to the division plane with high precision at onset of division. In all cases, information through oscillating signals is required to direct FtsZ to the cell-center through spatiotemporal regulation by coordinated action. How did these signals emerge? Scientists have proposed various models 


Biochemical oscillators
Cellular rhythms are generated by complex interactions among genes, proteins and metabolites. They are used to control every aspect of cell physiology, from signalling, motility and development to growth, division and death. 16 Biochemical oscillations occur in many contexts (such as metabolism, signalling and development) and control important aspects of cell physiology, such as circadian rhythms, DNA synthesis, mitosis and the development of somites in vertebrate embryos. In the 1950s and 1960s, the first clear examples of biochemical oscillations (in metabolic systems) were recognized in glycolysis.  Oscillators have systems-level characteristics (for example, periodicity, robustness and entrainment) that transcend the properties of individual molecules or reaction partners and that involve the full topology of the reaction network. 

First, negative feedback is necessary to carry a reaction network back to the ‘starting point’ of its oscillation. 
Second, the negative feedback signal must be sufficiently delayed in time so that the chemical reactions do not settle on a stable steady state. 
Third, the kinetic rate laws of the reaction mechanism must be sufficiently ‘nonlinear’ to destabilize the steady state. 
Fourth, the reactions that produce and consume the interacting chemical species must occur on appropriate timescales that permit the network to generate oscillations. 

The Min oscillator
Without MinD and MinE, MinC would simply inhibit cell division throughout the whole cell. MinD and MinE provide the localization cues that restrict MinC to zones near the cell poles and away from the cell midpoint, thus creating the desired bipolar concentration gradient of MinC. This gradient concentrates MinC near the cell poles and away from mid-cell, thus relieving the mid-cell site from its FtsZ disassembly activity. Remarkably, in E. coli this bipolar gradient of Min proteins is not static, but instead is characterized by wholesale migration of all three proteins from one cell pole to the other. MinC is not needed for this oscillation, but instead is a passenger on this endless ride, which cycles back and forth every 1 minute or so, depending on a number of factors, including temperature.


The Min bipolar gradient.
In E. coli, MinE moves toward complexes of MinC–MinD at one pole and stimulates the ATPase activity of MinD, causing MinC and MinD to cycle to the opposite pole. Non-ring FtsZ oscillates as well, in response to MinC. When a cell nears division, MinC and MinD pause at the septum, presumably to prepare for equal distribution into daughter cells and possibly to assist the Z ring in constriction. Finally, cells divide and each daughter cell has an oscillating Min system.

Molecular mechanism of the oscillation
MinD is a ParA family ATPase with a deviant Walker A motif and a carboxy-terminal amphipathic helix that, crucially, binds the cytoplasmic membrane only when MinD is in the ATP-bound form. MinD–ATP also forms a symmetrical dimer.


Molecular mechanism of the Min oscillation.
MinC and MinD both dimerize and form complexes that are capable of oligomerization. As MinE binds to MinD, it undergoes a conformational change, displaces MinC, and stimulates the ATPase activity of MinD. This converts MinD to its monomeric ADP-bound form, removing it from the membrane. MinE can then move on to remove other complexes or return to its previous conformation. MinC and MinD cycle to the opposite pole, followed by MinE. MinC is labeled only as ‘C’.

Upon binding MinE, which also has a membrane-binding amphipathic helix, MinD’s ATPase activity is stimulated, causing MinD in its ADP form to change its conformation, monomerize, and leave the membrane. This ATPase activity by the MinD dimer can be stimulated even when MinE binds only one of the MinD subunits in the dimer. MinE can, therefore, move rapidly from one MinD–ATP dimer to the next, dislodging each from the membrane as it goes. A new MinD polar cup is formed after rapid ATP exchange and highly cooperative binding of MinD–ATP molecules to anionic phospholipids. In cells with excess anionic phospholipids, MinD-ATP no longer can form a normal cup and instead forms multiple discrete foci throughout the membrane that appear and disappear. Although regenerated MinD–ATP could conceivably bind the membrane anywhere in the cell, including near the site from which it came, this binding would be transient because of the high concentration of membrane-bound MinE. Forming a new polar cup far away from MinE is therefore favoured, and it is this behaviour that is thought to drive the oscillation.

The oscillation is tuned to sense the geometry of a typical E. coli cell. If these rod-shaped cells become elongated, the Min proteins form multiple dynamic binding zones on the membrane that are regularly spaced, ∼7–10 μm apart. This spacing presumably represents the default distance that one MinD zone can stably form away from a MinE zone, which is longer than the 3–4 μm typical of an E. coli cell. In rod-shaped cells with branches, MinD will explore the different branches. Because only MinD and MinE are needed for the oscillation, the system mimics a nonlinear reaction-diffusion system.

Already in 1952, Alan Turing suggested a diffusion–reaction system as one mechanism to generate patterns of molecular concentrations 15

Purified MinD and MinE are able to migrate in waves and other interesting dynamic patterns along supported lipid bilayers.


(B) Spiral waves formed by Min proteins. (Left) Only labeled MinE is shown (MinD, 1 mM; MinE, 1 mM); (right) labeled MinD and MinE are shown(MinD, 1 mM; MinE, 1 mM), 
(C) Double spirals formed by Min proteins; only labeled MinE is shown (MinD, 1 mM; MinE, 0.5 mM). The star marks the center of the double spiral.

In general, bacteria multiply by binary fission in which the division septum forms almost exactly at the cell center. How the division machinery achieves such accuracy is a question of continuing interest. Cell division in Escherichia coli and Bacillus subtilis are the most thoroughly studied cell division mechanisms. The earliest visible event in cell division is the formation of a Z ring by FtsZ, a tubulin like protein, at the future septum site. The Z-ring appears to be an accurate marker for the position of the division site and is furthermore recognized by set of cell division proteins—the divisome. 17  MinE is a topological factor which, together with MinD, provides the localization signals that restrict MinC to zones near the cell poles and away from the cell centre.  The consequence of this extraordinary protein oscillation is that the concentration of MinC is highest at the cell poles and lowest at the mid-cell where the Z-ring appears and, subsequently, the septum forms.

Bacterial Min system, due to evolution? 
There are many different systems for division site recognition and it is likely that new systems are waiting to be discovered. Min systems exist in most but not all bacterial species, and also in the plastids of higher plants. In other bacteria, such as Caulobacter crescentus, there is a completely different mechanism in which the MipZ protein controls Z-ring formation by creating a bipolar gradient with its minimal concentration at the potential septation site, where FtsZ can assemble. The existence of two different Min systems is intriguing.  From the available data it is hard to infer which Min system evolved from which and it has been speculated that both Min systems evolved together in Gram-positive bacteria for alternate life cycles of vegetative growth and sporulation.

Speculation. As always....

a  

EGFR dimerization and activation. 
The inactive, tethered EGFR monomer extends when the ligand binds either to domains I or III, causing breakage of the link between the dimerization arm and rotation of the angle between domains II and III to bring ligand-binding domains I and III into close proximity allowing a simultaneous ligand binding. The extended conformation exposes the dimerization arm for interaction with another extended monomer. The dimerization arm contacts are ringed with a dashed line. Dimerization allows autophosphorylation of the intracellular kinase domains, leading to subsequent phosphorylation of tyrosine residues in the C-terminal tail. Phosphorylated tyrosine residues are indicated with closed circles.

b In biochemistry, an effector molecule is usually a small molecule that selectively binds to a protein and regulates its biological activity. In this manner, effector molecules act as ligands that can increase or decrease enzyme activity, gene expression, or cell signaling. 

A slice of cell and molecular biology: A cell signaling and cell
https://www.lehigh.edu/~inbios21/PDF/Fall2015/Ware_08282015.pdf

1. https://www.ncbi.nlm.nih.gov/pubmed/21901818
2. https://reasonandscience.catsboard.com/t2727-post-transcriptional-modifications-ptms-of-histones-affect-gene-transcription
3. http://sci-hub.tw/https://www.ncbi.nlm.nih.gov/pubmed/15652149/
4. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050905
5. http://sci-hub.tw/https://www.nature.com/articles/nrm1838
6. https://www.nature.com/articles/nsmb0610-641
7. http://sci-hub.tw/https://www.nature.com/articles/nsmb.1843
8. http://sci-hub.tw/http://science.sciencemag.org/content/320/5877/789
9. https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2958.2003.03321.x
10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC145461/
11. https://en.wikipedia.org/wiki/Min_System
12. https://howlingpixel.com/i-en/Min_System
13. http://www.els.net/WileyCDA/ElsArticle/refId-a0000294.html
14. https://www.sciencedirect.com/science/article/pii/S0960982213005873
15. https://www.sciencedirect.com/science/article/pii/S0014579314004876
16. http://sci-hub.tw/https://www.nature.com/articles/nrm2530
17. https://www.frontiersin.org/articles/10.3389/fmicb.2013.00378/full
18. http://adsabs.harvard.edu/abs/2014APS..MARD11004B

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1257459/

The signal transduction Code

https://reasonandscience.catsboard.com/t2745-how-signaling-in-biology-points-to-design#6311

The life of every organism depends crucially on networks of interacting proteins that detect signals and generate appropriate responses.

The external signals (known as first messengers) never reach the genes. They are invariably transformed into a different world of internal signals (called second messengers) and only these, or their derivatives, reach the genes. In most cases, the molecules of the external signals do not even enter the cell and are captured by specific receptors of the cell membrane, but even those that do enter (some hormones) must interact with intracellular receptors in order to influence the genes. The transfer of information from the environment to genes takes place therefore in two distinct steps: one from first to second messengers, which is called signal transduction, and a second path from second messengers to genes which is known as signal integration. The surprising thing about signal transduction is that there are hundreds of first messengers (hormones, growth factors, neurotransmitters, etc.), whereas the known second messengers are only four:

- cyclic AMP, 
- calcium ions,
- inositol trisphosphate, 
- diacylglycerol

First and second messengers, in other words, belong to two very different worlds, and this suggests immediately that signal transduction may be based on organic codes. This is reinforced by the discovery that there is no necessary
connection between first and second messengers because it has been proved that the same first messengers can activate different types of second messengers, and that different first messenger can act on the same type of second messengers. The experimental data, in brief, prove that external signals do not have any instructive effect. Cells use them to interpret the world, not to yield to it. Such a conclusion amounts to saying that signal transduction is based on organic codes, and this is, in fact, the only plausible explanation of the data, but of course, we would also like a direct proof. As we have seen, the signature of an organic code is the presence of adaptors, and the molecules of signal transduction have indeed the typical characteristics of the adaptors. The transduction system consists of at least three types of molecules: a receptor for the first messengers, an amplifier for the second messengers, and a mediator in between. The system performs two independent recognition processes, one for the first and the other for the second messenger, and the two steps are connected by the bridge of the mediator. The connection, however, could be implemented in countless different ways since any first messenger can be coupled with any second messenger, and this makes it imperative to have a code in order to guarantee biological specificity.
In signal transduction, in short, we find all three characteristics of the codes:

(1) a correspondence between two independent worlds; 
(2) a system of adaptors that give meanings to molecular structures; and 
(3) a collective set of rules that guarantee biological specificity. 

Rule-making is the process that executive and independent agencies use to create, or promulgate, regulations, and is done ALWAYS by conscient beings.  

The effects that external signals have on cells, in conclusion, do not depend on the energy or the information that they carry, but on the meaning that cells are pre-programmed give them with rules that we can rightly refer to as signal transduction codes.

Signal Transduction Codes and Cell Fate
In cells in general, regardless of their identity and functional status, the mediators of signal transduction (ST), the classic second messengers, are highly conserved: 

- calcium, 
- cAMP, 
- nitric oxide, 
- phosphorylation cascades, 

At the same time, they are significantly less numerous than the extracellular signals (or first messengers) they represent, suggesting that this universal conversion of signals into second messengers follows the conventional rules of an organic code.

Convention and biochemical rules mean a treaty, an agreement, a standard of presentation or conduct, and inherently the product of a mind, intelligence and conscience. In the case of Cells, it must be a mind that sets the convention, rules, implementation of precision of organic chemistry, constraints by flexible organization, a program that works like software, able to interpret, recognize, select and discriminate the incoming signals and cues, and react in conformity and correctly, making correct choices, behaviors and responses across many hierarchical levels. Signal transduction does, in fact, qualify as a selection-driven recognition phenomenon. The cell is a semiotic structure and signal transduction is a meaning-making” process. The effects that external signals have on cells do not depend on the energy and information they carry, but on the meanings that cells give them with rules that can be called signal transduction codes. The deterministic rules of biochemistry being constrained by higher order principles can only depart from mental intelligence. 

Nevertheless, the way these second messengers are integrated and the consequences they trigger change dramatically according to cell organization – its structure and function. Signal transduction goes beyond the generation of second messengers and is more as the ability of a cell in its different configurations to assign meaning to signals through discrimination of their context. In metabolism, cell cycle, differentiation, neuronal, and immune function the circuitry operating at cell level will proceed by the creation of conventional links between an increasing number of physiological activities, that is, changes in environment are progressively coupled to transcription patterns; transcription and replication patterns; transcription, replication, and differentiation patterns; and transcription, replication, differentiation, and functional patterns. 1

The main task to be performed by signal transduction codes is to couple environmental changes with the subnetworks controlling cell growth. In fact, the way transcription is organized in prokaryotes assures that transcription is modulated by environmental signs; two-component regulatory systems work like adaptors coupling the presence of an specific energy source in the environment (e.g. glucose) to the transcription of enzymes involved in its metabolic processing.

The physiological responses of cells to external and internal stimuli are governed by genes and proteins interacting dynamically in complex networks. Molecular regulatory networks can be accurately modelled in mathematical terms. These models shed light on the design principles of biological control systems.  2 When the information in any of these cases is laid out in graphical form the molecular network looks strikingly similar to the wiring diagram of a modern electronic gadget. Instead of resistors, capacitors and transistors hooked together by wires, one sees genes, proteins and metabolites hooked together by chemical reactions and intermolecular interactions. The temptation is irresistible to ask whether physiological regulatory systems and molecular circuitry can be understood in mathematical terms, in the same way, an electrical engineer would model a radio. 

Complex molecular networks, like electrical circuits, seem to be constructed from simpler modules: sets of interacting genes and proteins that carry out specific tasks and can be hooked together by standard linkages. Cellular functions, such as signal transmission, are carried out by ‘modules’ made up of many species of interacting molecules. 3 Living systems obey the laws of physics, chemistry, and information. 

The notion of function or purpose differentiates biology from other natural sciences. Organisms exist to reproduce, whereas, outside religious belief, rocks and stars have no purpose. Cells exist far from thermal equilibrium by harvesting energy from their environment. They are composed of thousands of different types of molecule. They contain information for their survival and reproduction. Their interactions with the environment depend in a byzantine fashion on this information, and the information and the machinery that interprets it are replicated by reproducing the cell. Most biological functions arise from interactions among many components. For example, in the signal transduction system in yeast that converts the detection of a pheromone into the act of mating, there is no single protein, but several, interacting with each other, in an interdependent manner, responsible for amplifying the input signal provided by the pheromone molecule. To describe biological functions, we need a vocabulary that contains concepts such as amplification, adaptation, robustness, insulation, error correction and coincidence detection. 

To decipher how the binding of a few molecules of an attractant to receptors on the surface of a bacterium can make the bacterium move towards the attractant (chemotaxis) will require understanding how cells robustly detect and amplify signals in a noisy environment.  General ‘design principles’ — profoundly shape the constraints of cellular kinetics and chemical reactions, and govern the structure and function of modules. The notion of function and functional properties separate biology from other natural sciences and links it to synthetic disciplines such as computer science and engineering. 

Complex molecular networks, like electrical circuits, seem to be constructed from simpler modules: sets of interacting genes and proteins that carry out specific tasks and can be hooked together by standard linkages. Simple signalling pathways can be embedded in networks using positive and negative feedback to generate more complex behaviours — toggle switches and oscillators — which are the basic building blocks of the exotic, dynamic behaviour shown by nonlinear control systems.  Signal-response elements, certain feedback and feedforward signals can create diverse types of responses: sigmoidal switches (buzzers), transient responses (sniffers), hysteretic switches (toggles), and oscillators (blinkers). Through these components, cells can perform complex regulations through its signalling networks.  There are only a few types of signal-response relationships. Irreversible transitions are associated with saddle-node bifurcations. Oscillations arise at Hopf bifurcations and infinite-period bifurcations. No matter how complicated the network or how rich its behaviour, the signal-response curve can always be decomposed into these three bifurcations and a few others.

In eukaryotes, signal transduction codes assure that environmental changes are coupled to transcriptional responses, but in addition, to changes to replication and division. Eukaryotic cells require coordination between cell growth, DNA replication, and cell division. In this context, the organization and correct temporal sequence of the cell cycle, with checkpoints that assure DNA integrity before, during and after its replication, is of utmost importance. 

in eukaryotes, cell growth and cell division form a unified program, the cell cycle, with at least three critical points (the G1/S, G2/M, and M/G1 transitions). In fact, the molecular apparatus controlling these transitions are proteins
called cyclins and the kinases they recruit and activate. The cyclins have an oscillatory expression pattern and a modular regulation by means of association with cyclin-dependent kinases (Cdks). It is the topology of the cyclin/Cdk network that enables environmental changes to be coupled to transcription, which thus integrates metabolic controls with DNA replication and cell division controls.

The cell cycle control system has been described in the following terms: 

“Progress through the cell cycle is viewed as a sequence of bifurcations. A small newborn cell is attracted to the stable G1 steady-state. As it grows, it eventually passes the saddle-node bifurcation where the G1 steady state disappears, and the cell makes an irreversible transition into S/G2. It stays in S/G2 until it grows so large that the S/G2 steady state disappears, giving way to an infinite period oscillation. Cyclin-B-dependent kinase soars, driving the cell into mitosis. The drop in Cdk1- cyclin B activity is the signal for the cell to divide, causing cell size to be halved and the control system is returned to its starting point, in the domain of attraction of G1 steady state.” 

The transcription topology associated with the eukaryotic cell cycle connects regulatory elements (cyclin/Cdk subnetwork interactions) with higher order motifs (by introducing positive and negative feedback loops) to create (or to select) stable response modes (toggle switches and oscillators associated with G1/S and G2/M, and M/G1, respectively). Response mode modules work together to coordinate otherwise separated cell physiology transitions; cell growth, DNA replication, and cell division.

In prokaryotes cell growth is metabolism-driven and cell division is cell growth-driven, whereas in eukaryotes the cell cycle (which includes cell growth and cell division) is metabolism driven. This is only possible because prokaryotes and eukaryotes have different signal transduction codes.

Which is another blow for common ancestry of eukaryotes and prokaryotes. 

An important point is that any system of signs has an abstract nature. Rather than being based in discrete unities of matter and energy, they use differences and values to build contextual meanings. Difference and value were first defined as informational dimensions In such context, he claims, differences are expressed as precise regulatory elements and motifs (i.e. nodes and attractors), and value, on the other hand, is expressed by the connectivity and relative positioning of elementary differences. It follows almost naturally to correlate a difference to a digital mode of communication-based on binary and discontinuous choices, and a value to the analogue mode based on
comparisons and qualitative choices.

Different signal transduction (ST) codes control cell growth, cell cycle, cell fate, and cell function, and in each of these codes, stabilities are reached by virtue of the dynamic properties of the code network which vary by degree. There is a precise interplay between digital and analogue communication modes inside and between each of these codes, and most importantly, each of these codes can be ascribed to a precise functional property or selected biological meaning.

1. The codes of life, Barbieri, page 289
2. http://sci-hub.tw/https://www.sciencedirect.com/science/article/pii/S0955067403000176
3. http://sci-hub.tw/https://www.nature.com/articles/35011540

Irreducible complexity has been debunked?

Let's see another awe-inspiring protein, which demonstrates, why the claim is false.
Multicellular organisms are characterized by

- specialized behaviours,
- appropriate messaging,
- stigmergy and
- apoptosis behaviours

Each eukaryotic cell participates simultaneously in all four principles.
Apoptosis, or Programmed Cell Death, is key to multicellular life and multicellular computing. Orchestrated apoptosis helps the growing embryo to sculpt many aspects of its final form. It is also a part of normal "maintenance."

The Akt-PI3K pathway is essential for cell survival as activated Akt proteins influence many factors involved in apoptosis, either by transcription regulation or direct phosphorylation.
Protein kinase B (PKB), also known as Akt, is a protein kinase that PLAYS A KEY ROLE in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration. Akt regulates cellular survival and metabolism by binding and regulating many downstream effectors.
Aberrant activation of Akt, either via PI3K or independently of PI3K, is often associated with malignancy. Studies have identified gene amplification of the Akt isoforms in many types of cancer, including glioblastoma, ovarian, pancreatic and breast cancers.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599004/

Our data indicate that specific mechanisms have evolved for signalling nodes, like PKB, to select between various downstream events.
Really??!!

Alignment of the subdomains VII and VIII of the kinase domains of Akt family from several organisms revealed
three evolutionarily conserved tyrosine residues Tyr315, Tyr326, and Tyr340, which are close to the activation loop of Akt kinases
http://sci-hub.tw/htt…//www.ncbi.nlm.nih.gov/pubmed/11445557

What does that mean? Conserved means, there was no evolutionary change. It means as well, that the protein cannot work if not in that configuration. zzzz....zzzzz......zzzzzz. It also means, that gradual evolution where each intermediate stage had to be functional would not work.

Akt Signaling Pathway
https://www.thermofisher.com/…/c…/akt-signaling-pathway.html

Akt/PKB signaling pathway
https://en.wikipedia.org/wiki/Akt/PKB_signaling_pathway…

Protein kinase B
https://en.wikipedia.org/wiki/Protein_kinase_B#Function

Evolution, or design?



https://www.thermofisher.com/br/en/home/life-science/antibodies/antibodies-learning-center/antibodies-resource-library/cell-signaling-pathways/akt-signaling-pathway.html

Transcription Factor signalling pathways

Transcription factors are DNA-binding proteins that regulate the expression of genes. In the process, they can increase or decrease the level of transcription of specific genes. Transcription factors influence the creation of proteins—which themselves can act as signalling molecules.

Transcription factors are proteins, required to make Transcription factor proteins. How did they emerge in the first place? Catch22?

Transcription factors (TFs) and their specific interactions with targets are crucial for specifying gene expression programs. 3

Akt Signaling Pathway
Akt regulates multiple biological processes including cell survival, proliferation, growth, and glycogen metabolism. Akt is a key player in cardiovascular disease through its role in cardiac growth, angiogenesis, and hypertrophy. 1 The Akt-PI3K pathway is essential for cell survival as activated Akt influences many factors involved in apoptosis, either by transcription regulation or direct phosphorylation. 2



Accurate models of the cross-talk between signaling pathways and transcriptional regulatory networks within cells are essential to understand complex response programs. 4 Perturbation of the cellular environment typically incites a vast and complex reaction that involves a multitude of proteins operating together to respond to the new condition.

Cellular phenotypes not only result from alterations in the genomic code, but also depend on the influences of multiscale networks of molecular interactions that regulate gene expression, protein abundance, epigenetic state, and signaling activity. 5








1. https://www.cellsignal.com/contents/science-cst-pathways/pi3k-akt-signaling-resources/science-pathways-akt
2. https://en.wikipedia.org/wiki/Akt/PKB_signaling_pathway
3. http://sci-hub.tw/https://www.sciencedirect.com/science/article/pii/S009286740800617X
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561877/
5. http://califano.c2b2.columbia.edu/modeling-cell-regulatory-networks/