Transmembrane receptor Intrinsic tyrosine kinase

Besides cytoplasmic protein kinases, membrane receptors can exert protein kinase activity. These so-called receptor tyrosine kinases (RTK) contain a ligandbinding extracellular domain, a transmembrane motif, and an intracellular catalytic domain with specificity for tyrosine residues. Upon ligand binding and subsequent receptor oligomerization, the tyrosine residues of the intracellular domain become phosphory-lated by the intrinsic tyrosine kinase activity of the receptor [3, 4]. The phosphotyrosine residues ftmction as docking sites for other proteins that will transmit the signal received by the RTK. 

Some transmembrane receptors possess intrinsic tyrosine kinase activity. These receptors are known as receptor tyrosine kinases. Ligand binding to an extracellular domain of the receptor is coupled to the stimulation of tyrosine kinase activity localized on a cytoplasmic receptor domain. The ligand binding domain and the tyrosine kinase domain are part of one and the same protein. 

Semm testing reveals circulating antibodies to acetylcholine receptors in approximately 90% of individuals with generalized myasthenia and in almost 70% of those with ocular symptoms only. False-positive results are rare, and the antibody titer does not correlate with the severity of symptoms. In those patients who are seronegative for antiacetylcholine receptor antibodies, which is about 6% of myasthenia gravis patients overall, anti-MuSK antibodies may be present. MuSK is a muscle-specific transmembrane protein with intrinsic tyrosine kinase activity. Anti-MuSK antibodies are almost never seen in patients who have antiacetylcholine receptor antibodies, and vice versa. 

In platelets, signaling is initiated primarily through members of the heterotrimeric G protein-coiqtled femily of leceptois (seven transmembrane domains) and through adhesion receptors, and the signaling involves activation of both Ser/Thr kinases and tyrosine kinases. Neither G protein-coiqtled receptors nor adhesion receptors have intrinsic tyrosine kinase activity. However, NRTKs (with SH2-, SH3-, and proline-rich domains) are activated and initiate tyrosine phosphorylation reactions that in turn lead to the recmitment of signaling molecules to certain locations in the cell. These tyrosine kinases may phosphorylate submembranous proteins including receptors for cytoplasmic domains or components of the submembranous cytoskeleton of adhesion receptor-cytoskeleton... 

Transmembrane receptors with intrinsic tyrosine kinase activity... 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

Fig. 5.5. General functions of transmembrane receptors. Extracellular signals convert the transmembrane receptor from the inactive form R to the active form R. The activated receptor transmits the signal to effector proteins next in the reaction sequence. Important effector reactions are the activation of heterotrimeric G-proteins, of protein tyrosine kinases and of protein tyrosine phosphatases. The tyrosine kinases and tyrosine phosphatases may be an intrinsic part of the receptor or they may be associated with the receptor. The activated receptor may also include adaptor proteins in the signaling pathway or it may induce opening of ion channels.

Phospholipase C, which occurs in different subtypes in the cell, is a key enzyme of phosphatide inositol metabohsm (for cleavage specificity, see Fig. 5.24). Two central signaling pathways regulate phosphohpase C activity of the cell in a positive way (Fig. 6.4). Phospholipases of type CP (PL-CP) are activated by G-proteins and are thus linked into signal pathways starting from G-protein-coupled receptors. Phosphohpases of type Y (PL-Cy), in contrast, are activated by transmembrane receptors with intrinsic or associated tyrosine kinase activity (see Chapter 8, Chapter 10). The nature of the extracellular stimuli activated by the two major reaction pathways is very diverse (see Fig 6.4), which is why the phosphohpase C activity of the cell is subject to multiple regulation. 

Fig. 6.4. Formation and function of diacylglycerol and Ins(l,4,5)P3. Formation of diacylglycerol (DAG) and Ins(l,4,5)P3 is subject to regulation by two central signaling pathways, which start from transmembrane receptors with intrinsic or associated tyrosine kinase activity (see Chapters 8 11) or from G-protein-coupled receptors. DAG activates protein kinase C (PKC, see Chapter 7), which has a regulatory effect on ceU proliferation, via phosphorylation of substrate proteins. Ins(l,4,5)P3 binds to corresponding receptors (InsPs-R) and induces release of Ca from internal stores. The membrane association of DAG, PtdIns(3,4)P2 and PL-C is not shown here, for clarity.

Enzyme receptors are transmembrane receptors with intrinsic enzymatic activity. Examples are the receptor tyrosine kinases (RTKs), which autophosphorylate their own tyrosine residues, such as the growth factor receptors and the insulin receptor. And, finally, there are the intracellular DNA sinding receptors. They bind lipophilic ligands that pass through the membrane. They address genes directly. Examples are the steroid hormone receptors (see Chapter 11). (This figure was donated by Professor Martin Lohse, University of Wurzburg.)... 

Receptor Single transmembrane a helix intrinsic protein tyrosine kinase activity in cytosolic domain... 

The cytoplasmic domains of all of these receptors have an intrinsic protein tyrosine kinase activity, and all the receptors have hydrophobic transmembrane sequences. Their extracellular regions are more variable in stmcture. Depending on the receptor, they may contain a range of domains, including (1) immrmoglobulin domains, (2) cysteine-rich motifs, (3) fibronectin type III repeats, and (4) EGF motifs. These can be present singly or in different combinations. Growth factor receptors are therefore examples of mosaic proteins. 

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