Cell Surface Receptors

Cell surface receptors can be grouped into ten types depending on their structure, kind of ligands they bind, process of activation and the cellular functions that they effect.

1. Integrins
   Integrins are transmembrane proteins that function as receptors. They contain alpha and beta subunits and get activated upon binding to ligands by undergoing a conformational change. Molecules of the extracellular matrix act as ligands. Interaction of Integrins with these molecules produces intracellular signals that prevent apoptosis and promote cell proliferation.
   
2. Cell-cell adhesion proteins (also act as receptors)
   Cell adhesion proteins contain extracellular domains that exhibit homo or heterophillic interactions. Cell adhesion molecules on the other cell or cytoskeletal proteins act as ligands. The best suited examples are Cadherin molecules. Cadherins are linked to the cytoskeleton by catenins and effect cell proliferation, differentiation and invasion, the exact mechanism by which they get activated it not clear.
   These two receptors recognize various signaling molecules with their extracellular domains, resulting in activation of their intracellular domains and mediate interactions between the cell and its environment in its near vicinity.
   
3. Tyrosine kinase Receptors.
   These receptors include Ig-like, FNIII-like, EGF-like etc., which bind to soluble signalling molecules with their domains extracellularly and possess a tyrosine kinase domain intracellularly. Ligands that regulate cell growth known as growth factors, e.g. PDGF, EGF, IGF, FGF, VEGF bind to these receptors Such receptors are activated by ligand-induced receptor dimerization or oligomerization,upon which the intracellular kinase domains are brought close together so that may activate each other through mutual phosphorylation.Such auto phosphorylation serves two important functions. Primarily, it confers conformational changes so that the active site becomes accessible to substrates. Secondly phosphorylated tyrosine residues, present mainly outside the kinase domain act as docking sites for intracellular signalling molecules with SH2 or PTP domains. Such receptors play a key role in functions like Cell survival, proliferation and motility.
   
4. Cytokines receptors
   Major ligands for these receptors are Interleukins, growth factors and erythropoietin. These receptors are characterized by the presence of WSXWS motifs extracellularly and box1, box2 motifs intracellularly, which interacts with Jak kinases. At the same time they lack intrinsic kinase activity and so as to compensate the deficit take the aid of cytoplasmic tyrosine kinases of the Janus kinase(JAK) family. Activation involves ligand-induced receptor dimerization or oligomerization, resulting in activation of JAKs and initiation of downstream signaling pathways. Moreover, cytokine receptors often form complexes with transmembrane signal transducers, such as gp130.and mainly effect cell survival and proliferation.
   
5. Antigen Receptors
   T and B cell antigen receptors as the name suggests recognize and bind to antigens (ligands) with their extracellular domains which exhibit the characteristic Ig like domains. Activation occurs by means of aggregation. Intracellularly the antigen-binding subunit forms a complex with invariant chains responsible for signaling containing antigen-recognition activation motifs (ARAMs) with phosphorylatable tyrosine residues that are involved in interactions with SH2 domain containing tyrosine kinases of the ZAP-70/Syk family
   
6. Serine / Threonine Kinase receptors.
   These receptors possess cysteine-rich extracellular domains and serine/threonine kinase domain intracellularly and are therefore called as Serine/Threonine kinases. Receptors form members of the transforming growth factor b (TGF b) family binding to TGF b, BMP and activins which have important functions during embryonal development. Activation of these receptors also involves ligand-induced oligomerization (hetero-tetramerization). The ligands bind simultaneously to two different types of serine/threonine receptors,referred to as type I and type II receptors. A hetero-tetrameric complex is formed,in which the type II receptor phosphorylates the typeI receptor, causing activation of its kinase. These receptors are involved in cell functions like growth inhibition, cell differentiation and apoptosis.
   
7. TNF Receptor like molecules.
   These receptors are trimeric molecules that contain cysteine rich portions extracellularly and death domains intracellularly. They bind to TNF and Fas ligands and form members of the tumor necrosis factor (TNF) family, which induce apoptotic and other signals in target cells.
   They bind to and trimerize receptors that are devoid of intrinsic kinase activity; many of the receptors of this class have a conserved motif in their intracellular parts, referred to as death domains, which mediate contact with the initial components in the proteolytic cascade leading to cell death.
   
8. Frizzled molecules
   These receptors, similar to G protein coupled receptors are seven pass transmembrane proteins (that span the membrane seven times -7TM).They act as receptors for members of the Wnt family, which are implicated in cell fate decisions and in cell proliferation. Ligand binding to Frizzled receptors activates the Dishevelled signal transducer, which inhibits phosphorylation and destruction of the transcription factor b-catenin, thereby allowing it to enter the nucleus and effect transcription. The exact mechanism by which the receptor gets activated is not clear.
   
9. Patched receptors
   These receptors are twelve pass transmembrane proteins that bind to ligands like hedgehog. However, ligand binding to its receptors does not always lead to direct activation of a signaling pathway. In the case of Hedgehog, which regulates morph idleness and many developmental events, binding to its multipassmembrane receptor Patched causes a derepression of Smoothened, a seven-transmembrane protein, and initiation of signalling from this protein.
   
10. G protein coupled Receptors
    These receptors span the cell membranes seven times and are coupled to G proteins constitute the largest known gene family with more than 1000 members, including odorant receptors and receptors inducing cell migration and proliferation. Ligands like lysophosphotidic acid (LPA), short peptides and odorants bind to these receptors causing a conformational change in the intracellular part of the receptor, leading to an exchange of GTP for GDP to the alpha subunit of the heterotrimeric G protein. The GTP-bonded alpha subunit then dissociates from the beta-gamma subunit complex, both of which act as downstream effect or molecules. There is no substantial evidence that receptor activation upon ligand binding occurs due to its oligomerization.
    
11. Ion channel Receptors
    Ligand-gated ion channels and ion pumps also have important roles in signal transduction, particularly in the nervous system and in muscle contraction. Nerve cells and muscle cells are considered as Excitable cells due to their ability to convert chemical or mechanical signals into electrical signals. Like all cells there exists a difference in the concentration of the ions across the plasma membrane and in response to a signal when the ion channels in the membrane open causing a flow of ions creating an electrical signal. Ion channels are multimeric transmembrane proteins that create a passage through the membrane which open and close in response to a chemical or mechanical signal. Amino acids lining the channels and the width of the channels confer selectivity in allowing a single type of ions to pass through. Upon binding of a ligand, conformational changes occur in the channel proteins resulting in the opening of channels. As a consequence, ions flow in and out of the cells to neutralizing the voltage or electrochemical gradient existing across the membrane due to the differential distribution of the ions. The flow of ions generates a electrical signal which is much faster than the chemical signals and thus ion channels open and close within a fraction of milliseconds whereas a GPCR would require approximately 20 minutes to elicit a similar response.
    Cell signaling can also happen without the need of cell surface receptors and external signals can also be received directly. For example, some lipid-soluble ligands, such as retinoic acid and steroid hormones, pass the plasma membrane and bind to intracellular receptors, which then translocate into the nucleus and regulate transcriptional events.

References

1. Chalfie, M. (2009) Neurosensory Mechanotransduction. Nature Reviews Molecular Cell Biology 10, 44–52
2. Li, J. et al .(2002) The Molecule Pages database. Nature 420, 716-717.
3. Hunter T (2000) Signaling-2000 and beyond. Cell: 113-127.
4. Pawson T and Scott JD (1997) Signaling through scaffold, anchoring and adaptor proteins. Science 278:2075-2080

Published date : 14 May 2014 02:04PM