Tyrosine kinase domain

Figure 13.24 Six subfamilies of receptor tyrosine kinases involved in cell growth and differentiation. Only one or two members of each subfamily are indicated. Note that the tyrosine kinase domain is interrupted by a "kinase insert region" in some of the subfamilies. The functional significance of the cysteine-rich and immunoglobulin-like domains is unknown.

Activation of the tyrosine kinase activity of the INSR is essential for the receptor function. The tyrosine kinase domain of the INSR is localized in the... 

Mohammadi, M., Schlessinger, J., and Hubbard, S. R., Structure of the FGF receptor tyrosine kinase domain reveals a novel autoinhibitory mechanism, Cell, 86, 577-578, 1996. 

Figure 10.7 The EGF receptor. The N-terminal, extracellular region of the receptor contains 622 amino acids. It displays two cysteine-rich regions, between which the ligand-binding domain is located. A 23 amino acid hydrophobic domain spans the plasma membrane. The receptor cytoplasmic region contains some 542 amino acids. It displays a tyrosine kinase domain, which includes several tyrosine autophosphorylation sites, and an actin-binding domain that may facilitate interaction with the cell cytoskeleton...

The cytoplasmic domain of the P-subunit displays three distinct sub-domains (a) the juxtam-embrane domain , implicated in recognition/binding of intracellular substrate molecules (b) the tyrosine kinase domain, which (upon receptor activation) displays tyrosine kinase activity (c) the C-terminal domain, whose exact function is less clear, although site-directed mutagenesis studies implicate it promoting insulin s mitogenic effects. 

The neurotrophins interact with two distinct cell surface receptor species [5,6,9] (Fig. 27-2). The neurotrophins bind to the Trk family of receptors, which serve as the principal signal transducer for this class of growth factors. The Trk receptors comprise a small, highly related family of molecules that possess an extracellular ligand binding domain that selectively interacts with the individual neurotrophin species. Trk A specifically binds NGF, TrkB interacts with BDNF and NT4/5, and TrkC preferentially binds NT3. Importantly, the Trk receptors have an intracellular tyrosine kinase domain that is activated upon neurotrophin binding. The kinase domains of the Trk family members are highly conserved and the Trks differ mainly in the structure of their extracellular domains. Trk receptor expression is limited to neurons and the... 

In sequence comparison, common protein domains such as the tyrosine kinase domain can mask other interesting matches (Sonnhammer and Durbin, 1994). Other weak but interesting matches may be lost in a large list of matches to the common domain. Thus domain databases are a useful way to identify these common domains so that they can be removed or masked in the sequence to allow the detection of weaker or less common domain similarities. 

The insulin receptor (top) is a dimer with subunits that have activatable tyrosine kinase domains in the interior of the cell (see p. 224). Binding of the hormone increases the tyrosine kinase activity of the receptor, which then phosphorylates itself and other proteins (receptor substrates) at various tyrosine residues. Adaptor proteins, which conduct the signal further, bind to the phosphotyrosine residues. 

Both receptors have seven immunoglobulin-like domains in their extracellular region, a single-membrane-spanning domain, and an intracellular split tyrosine kinase domain... 

Fig. 4. VEGF binds to the Ig-like binding domain ligand of I lk-1, activating the intracellular tyrosine kinase domain and instigating a signal transduction cascade that leads to angiogenesis.

The signaling mechanisms activated by neurotrophic factors, which include nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are fundamentally different from those discussed for G protein-coupled receptors and Ca " (Russell and Duman 2002). The neurotrophic factors bind to specific receptors, TrkA, TrkB, and TrkC (the name Trk is derived from their identification as troponin/receptor kinases from colon carcinoma) (Fig. 2). The Trk receptors contain an extracellular binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Two neurotrophic factor molecules are required for activation of a Trk receptor dimer, resulting in activation of the tyrosine kinase domains and phosphorylation of substrate proteins as well as autophosphorylation of the Trk receptor itself. 

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. 

Receptor tyrosine kinases are integral membrane proteins that have a hgand-binding domain on the extracellular side and a tyrosine kinase domain on the cytosohc side (see Fig. 8.1). The transmembrane portion is made up of just one structural element thus it is assumed that it crosses the membrane in an a-hehcal form. On the cytoplasmic side, in addition to the conserved tyrosine kinase domain, there are also further regulatory sequence portions at which autophosphorylation, and phosphorylation and dephosphorylation by other protein kinases and by protein phosphatases, can take place. 

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