Tyrosine kinase-containing receptors

Removal of flexible loops within the kinase domain has also been required for some kinases. Many receptor tyrosine kinases contain an additional domain within their C-terminal lobe, referred to as the kinase-insert domain. Removal of this highly charged domain was required to obtain data quality crystals of VEGFR2 [15]. 

Pajusola, K. Aprelikova, O. Korhonen, J. Kaipainen, A. Pertovaara, L. Alitalo, R. Alitalo, K. FLT4 receptor tyrosine kinase contains seven im-mimoglobulin-like loops and is expressed in multiple human tissues and cell lines. Cancer Res., 52, 5738-5743 (1992)... 

It remains unclear whether such approaches are truly general, in particular for proteins such as receptors that span different cellular compartments. For example, some receptor tyrosine kinases contain a kringle domain in their extracellular regions. Would such protocols predict common functions for intracellular tyrosine kinases and extracellular kringle-containing proteins, such as those of the hlood coagulation pathway Nevertheless, it is apparent that considerable functional constraints exist for domains to co-occur and that domain combinations are often very limited. 

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. 

The Src-homology 2 (SH2) domain is a protein domain of roughly 100 amino acids found in many signaling molecules. It binds to phosphorylated tyrosines, in particular peptide sequences on activated receptor tyrosine kinases or docking proteins. By recognizing specific phosphorylated tyrosines, these small domains serve as modules that enable the proteins that contain them to bind to activated receptor tyrosine kinases or other intracellular signaling proteins that have been transiently phosphorylated on tyrosines. 

PTKs can be subdivided into two large families, receptor tyrosine kinases (RTKs) and non-RTKs. The human genome encodes for a total of 90 tyrosine kinases of which 32 are nonreceptor PTKs that can be placed in 10 subfamilies (Fig. 1). All nonreceptor PTKs share a common kinase domain and usually contain several additional domains that mediate interactions with protein-binding partners, membrane lipids, or DNA (Table 1). These interactions may affect cellular localization and the activation status of the kinase or attract substrate proteins for phosphorylation reactions. 

Several cases are described (Cohen et ah, 1995) in which binding of an SH2-containing enzyme to an activated receptor tyrosine kinase leads to increased catalytic activity of the enzyme. Examples are the PI3-kinase and phospholipase Oy. The mechanism of activation is not clear. It is possible, however, that the basis is an allosteric mechanism, as is assumed for activation of Src tyrosine kinase. The Src kinase can be phosphoryla-... 

In addition to receptor tyrosine kinases, the cell also contains a number of tyrosine-specific protein kinases that are not an integral component of transmembrane receptors. These nonreceptor tyrosine kinases are localized in the cytoplasm at least occasionally or they are associated with transmembrane receptors on the cytoplasmic side of the cell membrane. They are therefore also known as cytoplasmic tyrosine kinases. The nonreceptor tyrosine kinases perform essential functions in signal transduction via cytokine receptors (see Chapter 11) and T cell receptors, and in other signaling pathways. 

Cytoplasmically localized protein tyrosine phosphatases have a catalytic domain and other structural elements that specify the subcellular localization and association with effector molecules. These structural elements contain sequence signals for nuclear localization, for membrane association and for association with the cytoskeleton (see Fig. 8.16). The presence of SH2 domains suggests that these molecules might interact with signaling pathways involving growth hormones and receptor tyrosine kinases. 

Green plants may have diverged from a common ancestor with animals 1.6 billion (1.6 x 109) years ago. How do the genomes of present-day plants and animals compare There are many similarities in basic metabolism. These arise from the intrinsic chemical properties and reactivities of cellular components and from the coevolution of plants and animals. Plants and animals also utilize similar structures and similar control of chromatin. However, in the control of development there are great differences.464 For example, the Arabidopsis genome contains no relative of the Drosophila Gurken, no receptor tyrosine kinases, no relatives of transcription factor NF-kB. However, there are similarities in parallel pathways utilized by plants and animals. 

Vicogne, J., Pin, J.P., Lardans, V., Capron, M., Noel, C. and Dissous C. (2003) An unusual receptor tyrosine kinase of Schistosoma mansoni contains a Venus Flytrap module. Molecular and Biochemical Parasitology 126, 51-62. 

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