Nonreceptor Tyrosine Kinases

Fyn is a nonreceptor tyrosine kinase related to Src that is frequently found in cell junctions. Die protein is N-myristoylated and palmitoylated and thereby becomes associated with caveolae-like membrane microdomains. Fyn can interact with a variety of other signaling molecules and control a diversity of biological processes such as T cell receptor signaling, regulation of brain function, and adhesion mediated signaling. 

S-acylated proteins include many GTP-binding regulatory proteins (G proteins), including most a subunits of heterotrimeric G-proteins and also many members of the Ras superfamily of monomeric G proteins, a number of G protein-coupled receptors, several nonreceptor tyrosine kinases, and a number of other signaling molecules, -acylation is posttranslational and reversible, a property that allows the cell to control... 

Protein tyrosine kinases Nonreceptor tyrosine kinases Cytoplasmic tyrosine kinases Tyrosylprotein kinase Hydroxyaryl-protein kinase... 

BCR-ABL Codes for a nonreceptor tyrosine kinase Chronic myelogenous leukemia... 

Despite the similar functions of each isozyme, only two regions of amino acid homology exist (X and Y), one of 150 and a second of 120 amino acid residues, which are 54% and 42% identical among the isozymes but are differentially localized within each enzyme (Fig. 20-3). The X and Y domains form the catalytic core of the enzyme. A characteristic of the (3 and 8 isoforms is that relatively few amino acids (40-110) separate the X and Y entities, whereas a much larger separation is observed for the PLCy isoform (approx. 400). In addition, in PLCy, the region between X and Y contains amino acid sequences that are found in nonreceptor tyrosine kinases (SH2 and SH3 domains). All four isoforms possess pleckstrin homology (PH) domains. The latter are considered to enable the enzyme to become tethered to the plasmalemma via an interaction with PI(4,5)P2. In addition, all PLC isoforms possess an E-F hand domain, which is located between PH and X domains, and a C2 domain, which is located close to the Y domain. 

The acylated peptides (Myr)GCX-Bimane 31 a-e (X = G, L, R, T, V), which are found in certain nonreceptor tyrosine kinases and ct-subunits of several heterotrimeric G-proteins, were synthesized in solution using common solution-phase peptide synthesis with X-myristoylglycine as a building block. These model peptides were used for acylation studies with palmitoyl-CoA in phospholipid vesicles at physiological pH. For such uncatalyzed spontaneous reactions only a modest molar excess of acyl donor species (2.5 1) was necessary. Unprotected side chains of threonine or serine are not interfering with this S-acylation (Scheme 14). 

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. 

Structure and General Function of Nonreceptor Tyrosine Kinases... 

Permanent or transient association with subcellular structures, and variable subcellular distribution, are characteristic for the cytoplasmic tyrosine kinases. Tire nonreceptor tyrosine kinases are intracellular effector molecules that can associate with specific substrates during the process of signal transduction and activate these by tyrosine phosphorylation, to pass on the signal. Many of the functions of the nonreceptor tyrosine kinases are performed in the iimnediate vicinity of the cell membrane, whether a signal is received from an activated membrane receptor or a signal is passed on to a membrane-associated protein. 

In Fig. 8.14, the structures of some nonreceptor tyrosine kinases are shown schematically (review Taniguchi, 1995). Tire nonreceptor tyrosine kinases can be divided into different families based on sequence homology the Src family is the best characterized. In addition to the catalytic domain, the nonreceptor tyrosine kinases often have SH2 and SH3 domains responsible for specific association with substrate proteins. Nonreceptor tyrosine kinases that contain both SH2 and SH3 domains may be involved in signal transduction in larger protein complexes. 

Two of the nonreceptor tyrosine kinases are highlighted, Src kinase and Abl kinase. 

Like many other nonreceptor tyrosine kinases, Abl tyrosine kinase may be converted by mutations into a dominant oncoprotein and thus contribute to tumor formation. Abl tyrosine kinase was first discovered as the oncogene of murine Abelson leukemia virus. Chronic myelogenic leukemia in humans is cause by a chromosome translocation in which a fusion protein is created of Abl tyrosine kinase and a Bcr protein (c Chapter 14). The result is a greatly increased tyrosine kinase activity, to which a causal role in occurrence of this leukemia is attributed. 

Like many other ligand-gated ion chaimels, the charmel gating properties of the NMDA receptor are regulated by phosphorylation. The NR2 subimit of the receptor contains many Tyr phosphorylation sites in the cytoplasmic region and it has been shown that receptor activity is stimulated by Tyr phosphorylation. Cytoplasmic nonreceptor tyrosine kinases of the Src family are responsible for the Tyr phosphorylation. Thus, a specific association with PSD-95, and thereby mediation of phosphorylation of NR2, has been demonstrated for the Fyn kinase, a member of the Src kinase family (Tezuka et al., 1999). Thus, the nonreceptor tyrosine kinase has an important role in regulation of synaptic activity and plasticity. A model for Fyn association with the NMDA receptor/PSD95 complex is shown in Fig. 16.11. 

The stimulation of vascular and cardiac growth by Ang II is mediated by other pathways, probably receptor and nonreceptor tyrosine kinases such as the Janus tyrosine kinase Jak2 and increased transcription of specific genes (see Chapter 2). 

Morpholin-4-yl-piperizyl) quinazoline derivatives, (I), prepared by Kanter (2) were effective as kinase phosphorylation inhibitors and used in the treatment of proliferative diseases such as arteriosclerosis, vascular reobstruction after percutaneous coronary angioplasty, and bypass operation cell-proliferative. Quinazoline derivatives, (n), prepared by Lambert (3) were effective against the Src family of nonreceptor tyrosine kinases inhibitors and used in the treatment of uncontrolled cellular proliferation. 

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