Protein tyrosine kinases characteristics

The oncogene v-erbB, unlike c-erbB, codes for a shortened form of the EGF receptor protein. Usually the binding of EGF is required to turn on the tyrosine kinase activity of the EGF receptor protein, the one coded by c-erbB. However, the tyrosine kinase activity of the receptor derived from v-erbB is switched on permanently, even in the absence of EGF. The uncontrolled grqwth characteristic of cancer cells results. 

Phosphohpases of type Cy are activated by receptor tyrosine kinases (see Chapter 8), and thus phosphohpase Cy is involved in growth factor controlled signal transduction pathways. The receptor tyrosine kinases (see Chapter 8) phosphorylate the enzyme at specific tyrosine residues and initiate activation of the enzyme. Characteristic for the structure of phospholipase Cy is the occurrence of SH2 and SH3 domains (see Chapter 8). These represent protein modules that serve to attach further partner proteins. 

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. 

Another family of protein kinases involved in signal transduction via cytokines includes the Janus kinases (Jak kinases). At least four different Jak kinases are known in mammals (Jakl, Jak2, Jak3 and Jak4). A characteristic feature of the structure of Jak kinases is the occurrence of two tyrosine kinase domains (Fig. 11.5). However, only... 

Protein kinases can be classified according to the amino acid residue that is phosphorylated in the cellular process. Consequently, there are tyrosine-specific kinases and serine/threonine kinases. Tyrosine kinases are a family of tightly regulated enzymes, and the aberrant activation of various members of this family is one of the hallmarks of cancer. Tyrosine phosphorylation has been linked to multiple cell growth and differentiation pathways. Imatinib mesylate (1) is a tyrosine kinase inhibitor (TKI). An important characteristic of imatinib mesylate (1) is that it is an ATP-competitive inhibitor. It binds at the ATP binding site and blocks ATP binding thereby inhibiting kinase activities. 

Fig. 14.5 The TCR Complex is associated with a number of T< ll specific membrane-spanning proteins.31 The antigen receptors and the co-receptors, CDS, CD4, and CDS, together with associated enzymes, tyrosine kinases and phosphatases, form the actual signalling complex. The cytoplasmic chains of the co-receptor molecules have characteristic consensus sequences, the ITAMs (immunoreceptor tyrosine activation motife). Each of the invariant -chains and the CD3-y,8, e chains, contain 1-3 copies of the RAM motife. The structure of the TCR-signalling complex still needs to be clarified.

The endothelins receptors are of the seven-transmembrane G-protein-coupled type, and couple mainly through the InsPs/DAG systems, though other mechanisms (including activation of tyrosine kinases and mitogenesis) may be involved. There are at least two receptor types encoded by different genes on different chromosomes. Also, there are species-dependent isoforms. The characteristics of the two receptors are as follows. 

InsPa receptors are phosphorylated in cells following activation of protein kinase A (PKA) (Yamamoto et al. 1989 Joseph and Ryan 1993),protein kinase G (PKG)(Komalavilas and Lincoln 1994), and tyrosine kinase (Harnick et al. 1995). Interestingly, splice variants of the type-I InsPa receptors with different phosphorylation characteristics exist a shorter... 

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