Src family, of protein tyrosine kinases

In an in vitro model, exposure of lymphoma cells to rituximab resulted in the activation of the Src-family of protein tyrosine kinases (13), leading to the phosphorylation of PLCy2, which induces calcium influx and activates caspase 3, resulting in promotion of apoptotic cell death (8,14). Another in vitro model showed that exposure to rituximab resulted in the sustained phosphorylation of p38-MAPK, JNK, and ERK kinases... 

Vetrie, D., I. Vorechovsky, P. Sideras, J. Holland, A. Davies, F. Flinter, L. Hammarstrom, C. Kinnon, R. Levinsky, M. Bobrow, and et al. 1993. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 361 226-233. 

Thioacylated proteins contain fatty acids in thioester linkage to cysteine residues [7-9] (Fig. lA). Protein thioacylation is frequently referred to as palmitoylation, although fatty acids other than palmitate are found on thioacylated proteins. Membrane proteins as well as hydrophilic proteins are thioacylated, the latter, in many cases, acquiring the modification when they become associated with a membrane compartment as a result of initial N-myristoylation or prenylation. Examples include G-protein coupled receptors, the transferrin receptor, the cation-dependent mannose-6-phosphate receptor, and hydrophilic proteins such as members of the Src family of protein tyrosine kinases (e.g., p59h " and p56 ) as well as H-Ras, N-Ras, and the synaptic vesicle protein SNAP-25. The yeast palmitoyl proteome, i.e., the collection of all S-acylated proteins in yeast, was recently defined via a comprehensive proteomics approach (A.F. Roth, 2006). It consists of 50 proteins including... 

Src is the prototype of the superfamily of protein tyrosine kinases and was one of the first protein kinases to be characterized by various genetic, cellular, and structure-function studies to help imderstand its role in signal transduction pathways as well as in disease processes, including cancer, osteoporosis, and both tumor- and inflammation-mediated bone loss [28-38]. In fact, studies on Src provided some of the first evidence correlating protein kinase activity and substrate protein phosphorylation in the regulation of signal transduction pathways relative to normal cellular activity as well as mahgnant transformations. Src family kinases include Fyn, Yes, Yrk, Blk, Fgr, Hck, Lyn,... 

Tyrosine kinases are enzymes present in multicellular eukaryotes which catalyse the phosphorylation of tyrosine residues by ATP. and all participate as signalling elements in transduction pathways. There are two types of protein tyrosine kinase growth factor receptors, and cytoplasmic protein tyrosine kinases, which include src family kinases and the JAK family kinases. The growth factor receptors are... 

Figure 13.32 Regulation of the catalytic activity of members of the Src family of tyrosine kinases, (a) The inactive form based on structure determinations. Helix aC is in a position and orientation where the catalytically important Glu residue is facing away from the active site. The activation segment has a conformation that through steric contacts blocks the catalytically competent positioning of helix aC. (b) A hypothetical active conformation based on comparisons with the active forms of other similar protein kinases. The linker region is released from SH3, and the activation segment changes its structure to allow helix aC to move and bring the Glu residue into the active site in contact with an important Lys residue.

Like all immunoreceptor family members, FceRI lacks intrinsic tyrosine kinase activity. IgE and antigen-induced crosshnking of FceRI initiates a complex series of phosphate transfer events via the activation of non-receptor Src, Syk and Tec family protein tyrosine kinases (fig. 1). The Src family kinase Lyn, which associates with the FceRI p subunit in mast cells, transphosphorylates neighboring FceRI ITAMs after receptor aggregation [7, 26]. Once phosphorylated, the p chain ITAM binds to the SH2 domain of additional Lyn molecules, while the phosphorylated y chain ITAM recruits Syk to the receptor complex, where it is activated by both autophosphorylation and phosphorylation by Lyn [2, 7,15, 26]. 

In spite of having no intrinsic catalytic domains, activation of T lymphocytes commences with tyrosine phosphorylations, activation of PLC-v with production of IP3 and DAG, and elevation of cytosolic free Ca2+. Thus, the consequences of receptor ligation are not dissimilar from those induced by the receptors for EGF or PDGF. An early study trying to explain the induction of tyrosine kinase activity resulted in the discovery of the nonreceptor protein tyrosine kinase Lck (p56lck), a T-cell-specific member of the Src family. Lck is associated with the cytosolic tail of CD4 (in helper T cells) or CD8 (in cytotoxic T cells) (Figure 8.14). As mentioned, the extracellular domains of these... 

Nonreceptor protein tyrosine kinases contain a catalytic domain, as well as various regulatory domains important for proper functioning of the enzyme. NRPTKs are found in the inner leaflet of the plasma membrane, cytosol, endosomal membranes and nucleus. These include the Src, Jak, Abl, Tec, Ack, Csk, Fak, Fes, Frk and Syk subfamilies (Fig. 24-3). Since a great deal is known about the structure and regulation of the Src family tyrosine kinase, we will use it to illustrate the principles in NRPTK signaling unique features in other subfamilies will be indicated... 

Myristoylation is generally considered a constitutive process and a permanent modification. As shown above the myristoic anchor may function as a switch during regulated membrane anchoring. Examples for myristoylated proteins are the cytoplasmic protein tyrosine kinases (family of the Src-kinases, chapter 8), as well as the a-subunit of the heterotrim eric G-proteins (chapter 5). 

Examples of receptor-associated tyrosine kinases are given in Table 8.1. Most of the associated protein tyrosine kinases belong to the family of Src kinases (see 8.3) and the Jak kinases (see 11.1.3). 

The Rous sarcoma virus oncogene v-src and a family of related oncogenes are derived from protein tyrosine kinases that are attached with the aid of a... 

The Src homology 3 (SH3) domain of a-spectrin was the first SH3 domain structure to be solved (Musacchio et al., 1992). The domain was initially identified as regions of similar sequence found within signaling proteins, such as the Src family of tyrosine kinases, the Crk adaptor... 

OKADA M, NADA S, YAMANASHIY, YAMAMOTO T, NAKAGAWA H (1991) CSK a protein-tyrosine kinase involved in regulation of src family kinases. Journal of Biological Chemistry, 266,24249-24252. 

As a consequence of ligand binding to cytokine receptors, activation of a tyrosine kinase activity, which is not part of the receptor protein, is observed. In most cases this tyrosine kinase is permanently associated with one of the subunits ofthe receptor, and ligand-induced restructuring or hetero-oligomerization ofthe receptor induces activation of this tyrosine kinase. The tyrosine kinases most frequently associated with cytokine receptor subunits belong to the family of Janus kinases. However, protein tyrosine kinases ofthe Src family like Lck, Fyn and Tyk have also been shown to be direct downstream components of the cytokine receptors (see Section 11.2.2). 

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