Protein-protein interactions define specificity in signal transduction.

By Tony Pawson, Piers Nash. Genes & Development, 2000

756 citations recorded by the source corpus.

Virtually every aspect of cellular function within a metazoan organism, including proliferative status, metabolism, gene expression, cytoskeletal organization, and indeed the cell’s very survival, is dependent on external signaling molecules, either in the form of soluble hormones or proteins anchored to the surface of an adjacent cell or the extracellular matrix (ECM). These factors exert their effects either by binding receptors displayed on the surface of the cell or, in the case of compounds such as steroids, by traversing the plasma membrane and directly engaging intracellular receptors. In addition, these external signals can be linked to intrinsic cues that regulate events such as polarity and asymmetric cell division, and that monitor the molecular composition of the cell, and therefore determine whether suitable conditions prevail for cell growth and division. Over the last two decades, we have achieved considerable understanding of the mechanisms by which signals are conveyed from receptors at the plasma membrane to their targets in the cytoplasm and nucleus. At heart, this is a problem of molecular recognition. Hormones must bind selectively to their receptors and these in turn must interact with specific cytoplasmic targets. To understand signal transduction in a general sense, it is important to know whether different biochemical pathways use related molecular devices to control cellular behavior. To understand specificity in signaling, we need to know how receptors interact with particular targets and how the proteins of one pathway can be insulated from related signaling components. At the same time, it is important to learn how distinct signaling pathways communicate with one another, since the entire cell must ultimately function as a single unit whose different elements respond in an organized fashion to external signals. A cell in the body will be exposed to many different stimuli, which it must integrate into a coherent response. Furthermore, although a rather large fraction of genes within nucleated cells appear to function in the processes of signal transduction and cellular organization (Plowman et al. 1999), it is still remarkable that only a few thousand gene products can control the sophisticated behaviors of many different cell types. This immediately suggests that signaling proteins must act in a combinatorial fashion, since there are insufficient proteins for each to have a single biological role. For example, there are billions of neurons in the human brain, each of which must project its axon to the appropriate target, let alone undertake the complex biochemical events associated with neurotransmission and synaptic plasticity. Clearly, the signaling molecules that function in the process of axon guidance must act in a combinatorial way to generate the extreme complexity of the human nervous system. Here we will address some of the underlying biochemical mechanisms through which specificity is generated during signal transduction, and pursue the means by which signaling molecules may act in combination to generate complex biological responses.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/28e3341de0ddd6a0f5e338263a1f4d13e59422ec

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Citations in the corpus

Targeting PI3K/Akt/mTOR Signaling in Cancer (2014, background): “of other pro-apoptotic factors, such as Fas-ligand (FasL) (7, 8).”
Trk receptors: mediators of neurotrophin action. (2001, background): “Phosphorylation of the other residues promotes signaling by creating docking sites for adaptor proteins that couple these receptors to intracellular signaling cascades, including the Ras/extracellular signal regulated kinase (ERK) protein kinase pathway, the phosphatidylinositol-3-OH kinase (PI3K)/A”
Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry (2002, background): “gif" NDATA ITEM> ]> The recent abundance of genome sequence data has brought an urgent need for systematic proteomics to decipher the encoded protein networks that dictate cellular functio”
HINT: High-quality protein interactomes and their applications in understanding human disease (2012, background): “Most proteins perform their functions through interactions [4].”
Histone and chromatin cross-talk. (2003, background): “This docking of effectors to post-translationally modified chromatin is reminiscent of the modular interactions in other signaling pathways (see for example the recruitment of SH2 domains to phosphotyrosines; for references see [10]).”
Neurotrophins: roles in neuronal development and function. (2001, background): “Phosphorylation of the other tyrosine residues promotes signaling by creating docking sites for adapter proteins containing phosphotyrosine-binding (PTB) or src-homology-2 (SH-2) motifs (reviewed in Pawson & Nash 2000).”
The mechanism of phospholipase C-γ1 regulation (2000, background): “The SH2 domains recognize phosphotyrosine sequences in other proteins (Gergel et al., 1994; Pawson 1994; Sillman and Monroe, 1995; Valius et al., 1995; Yablonski et al., 1998; Poulin et al., 2000), while the SH3 domain mediates interactions with proteins containing prolinerich sequences (PXXP motif)”
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