Evo Devo

Evolutionary development - at the biological interface between genetic regulatory mechanisms and biological evolution.

molecular switches

Long before nanotechnology, biochemical molecular switches evolved to function within signal transduction pathways that control cellular differentiation, the cell cycle and cellular proliferation.

: cAMP-dependent protein kinase : MAP kinases : PKA : PKCs : protein kinase A : protein kinase Cs : Ras : receptor tyrosine kinases : serine/threonine kinases : Tissues :

As central components of cell signaling networks, receptor tyrosine kinases (RTKs) play crucial roles in physiological processes, such as embryogenesis, differentiation, neurite outgrowth, cell proliferation, anti-apoptotic signaling and death of cells (apoptosis).

The serine/threonine kinases comprise a large family, which serve in in signal transduction pathways for receptors of the TGF-β ligand superfamily.

Protein kinase A, or cAMP-dependent protein kinase is an enzymes whose catalytic (protein phosporylating) activity is modulated by cAMP levels. PKA is highly conserved with RTKs.

Protein kinase Cs, are enzymes that exhibit specific patterns of tissue expression and activation and are maximally active in the presence of calcium ion and diacylglycerol. PKC activity is mediated by receptors that are coupled to activation of phospholipase C-gamma (PLC-gamma), which contains SH2 domains that enable it to interact with tyrosine phosphorylated RTKs. Phospholipases D and A2 (PLD, PLA2) sustain the activation of PKC through their hydrolysis of membrane phosphatidylcholine (PC). Activation of PLC-gamma results in hydrolysis of membrane phosphatidylinositol bisphosphate (PIP2), which leads to an elevation of intracellular diacylglycerol (DAG) and inositol trisphosphate (IP3), which interacts with intracellular membrane receptors to effect release of stored calcium ions. PKCs are involved in signal transduction pathways initiated by specific hormones, growth factors and neurotransmitters.

Mitogen activated protein kinases (MAP kinases), act as switch kinases that transmits information of increased intracellular tyrosine phosphorylation to that of serine/threonine phosphorylation. MAP kinases are also called ERKs for extracellular-signal regulated kinases, microtubule associated protein-2 kinase (MAP-2 kinase), myelin basic protein kinase (MBP kinase), ribosomal S6 protein kinase (RSK-kinase) and EGF receptor threonine kinase (ERT kinase). Maximal MAP kinase activity requires phosphorylation of both tyrosine and threonine residues.

Ras genes encode proteins of the Ras superfamily, which includes Rab, Ras, and Rho (including Rho-GTPase) families. Proteins of the Ras superfamily are important molecular switches in signal transduction pathways. Ras proteins are involved in cell adhesion, apoptosis, cell migration, cytoskeletal integrity, cell proliferation, and, when unregulated, neoplasia.

Tissues / Functions:

Cytoskeleton:
The phagosome cAMP/PKA system behaves as a molecular switch that regulates phagosome actin and maturation in macrophages.[pm]

Neural tissue:
Synapsins are synaptic vesicle-associated phosphoproteins involved in the regulation of neurotransmitter release and synapse formation; they are substrates for multiple protein kinases that phosphorylate them on distinct sites. Phosphorylation of synapsin domain A is essential for the synapsin-induced enhancement of neurotransmitter release, suggesting that endogenous kinases phosphorylating the synapsin domain play a central role in the regulation of the efficiency of the exocytotic machinery.[s & fft-s] Cyclic AMP (cAMP) promotes neurite outgrowth in a variety of neuronal cell lines through the activation of protein kinase A (PKA). The nerve growth-promoting action of cAMP/PKA is mediated in part by the phosphorylation of synapsins at a single amino acid residue.[r] :

Neuregulin gene switch for myelin production.

Renal:
Mutations in the gene encoding the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and hyperkalemia. Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K(+) secretion by altering the mass and function of the DCT through its effect on NCC.[p]

Tumorigenesis:
Ras genes encode proteins of the Ras superfamily, which are important molecular switches in signal transduction pathways. Ras proteins are involved in cell adhesion, apoptosis, cell migration, cytoskeletal integrity, cell proliferation, and, when unregulated, neoplasia.The superfamily includes Ras, Rho, and Rab families. The Rho family includes Rho-GTPase.

The Ras GTPases act as binary switches for signal transduction pathways that are important for growth regulation and tumorigenesis. Despite the biochemical simplicity of this switch, Ras proteins control multiple pathways, and the functions of the four mammalian Ras proteins are not overlapping. One recently emerging model suggests that a single Ras protein can control different functions by acting in distinct cellular compartments. The fission yeast Schizosaccharomyces pombe expresses only one Ras protein that controls two separate evolutionarily conserved pathways. Whereas Ras localized to the plasma membrane selectively regulates a MAP kinase pathway to mediate mating pheromone signaling, Ras localized to the endomembrane activates a Cdc42 pathway to mediate cell polarity and protein trafficking -providing unambiguous evidence for compartmentalized signaling of Ras.

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