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Review
, 20 (13)

Conceptual Evolution of Cell Signaling

Affiliations
Review

Conceptual Evolution of Cell Signaling

Arathi Nair et al. Int J Mol Sci.

Abstract

During the last 100 years, cell signaling has evolved into a common mechanism for most physiological processes across systems. Although the majority of cell signaling principles were initially derived from hormonal studies, its exponential growth has been supported by interdisciplinary inputs, e.g., from physics, chemistry, mathematics, statistics, and computational fields. As a result, cell signaling has grown out of scope for any general review. Here, we review how the messages are transferred from the first messenger (the ligand) to the receptor, and then decoded with the help of cascades of second messengers (kinases, phosphatases, GTPases, ions, and small molecules such as cAMP, cGMP, diacylglycerol, etc.). The message is thus relayed from the membrane to the nucleus where gene expression ns, subsequent translations, and protein targeting to the cell membrane and other organelles are triggered. Although there are limited numbers of intracellular messengers, the specificity of the response profiles to the ligands is generated by the involvement of a combination of selected intracellular signaling intermediates. Other crucial parameters in cell signaling are its directionality and distribution of signaling strengths in different pathways that may crosstalk to adjust the amplitude and quality of the final effector output. Finally, we have reflected upon its possible developments during the coming years.

Keywords: cell signaling; crosstalk; evolution; ligand; receptor; signal transduction.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cellular signaling controls various aspects of multicellular life forms. Not only the key biological processes such as cell division, differentiation, growth, and cell-cycle transition, but also specialized cell-specific functions such as neurotransmission, pathogen-sensing, phagocytosis, and antigen-presentation are controlled by specific signaling pathways. The process of autophagy and nutrient cycling and recycling are some accessory pathways that are triggered by definitive signaling cues.
Figure 2
Figure 2
A holistic view of the various cell-surface and intracellular receptors, their associated intracellular components, and downstream effects (Note—Receptors and protein structures are adapted from PDB-http://pdb101.rcsb.org).
Figure 3
Figure 3
Represents the different protein domains and their categorization based on binding with other molecules and their biological functions. (Note—Sources: http://www.ebi.ac.uk/interpro/; http://www.cellsignal.com).
Figure 4
Figure 4
(A) Binding of the ligand to a receptor on the plasma membrane or its translocation to endosomes can trigger diverse signaling outputs. For example, binding of LPS to TLR4 receptor on the plasma membrane or on its translocation to the endosome can lead to the activation of distinct signaling intermediates and eventually specific transcription factors. (B) A variety of molecules (solid- adhesion molecules, extracellular matrix components; soluble factors) can elicit cell signaling. Receptor-ligand coupling triggers the enzymatic machinery that activates various transcription factors, which regulates gene expression.
Figure 5
Figure 5
Overview of intracellular vesicular trafficking-cellular organelle rough endoplasmic reticulum (RER) Coat protein I and Coat protein II form vesicles that mediate cargo transport between Golgi to ER and ER to Golgi, respectively. Of the major endocytosis pathways, clathrin-coated vesicles form the early endosomes that mature into late endosomes that subsequently fuse with lysosomes leading to protein recycling. Clathrin, by associating with Adaptor protein (AP) 1 and 2, extends vesicular transport that involves trans-Golgi network. AP3 however, transports proteins to lysosomes and other related organelles. Moreover, receptor endocytosis (GPCR) can occur in clathrin-dynamin-dependent manner. Caveolin also forms endosomal vesicles and joins in the classical endocytic pathway. Phagocytic cells engulf pathogens and effect its lysosomal degradation.
Figure 6
Figure 6
(A) In coincident detector mechanism; (B) gated mechanism; (C) feedback mechanism (positive and negative).

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