Fyn tyrosine kinase

Kierszenbaum AL, Rivkin E, Talmor-Cohen A, Shalgi R, Tres LL. 2009. Expression of full-length and truncated Fyn tyrosine kinase transcripts and encoded proteins during spermatogenesis and localization during acrosome biogenesis and fertilization. Mol Reprod Dev 76(9) 832-843. 

Talmor A, Kinsey WH, Shalgi R. 1998. Expression and immunolocalization of p59c-fyn tyrosine kinase in rat eggs. Dev Biol 194(l) 38-46. 

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. 

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,... 

In addition to the Lck kinase, other tyrosine kinases are activated on ligand binding to the IL-2 receptor. These are Fyn kinase and the Janus kinases Jakl and Jak3. 

An inhibitory phosphorylation of the tyrosine kinases Lck and Fyn is also important for signal transduction, and this is performed by Csk kinase. This phosphorylation takes place at the C-terminus of Lck and inhibits the kinase activity in a similar way to that already structurally illustrated for Src kinase (see 8.3.2). 

Fig. 16.11. Model of the association of Fyn kinase with the NMDA receptor The NMDA receptor is shown as a tetramer of NRl and NR2 subunits. The C-terminal tail of NR2 interacts with PDZ2 of PSD-95. The protein tyrosine kinase Fyn is assumed to bind to PDZ3 of PSD-95 via its SH2 domain. Fyn also is anchored to the ceU membrane via its myristoylated N-terminus. GK guanylate kinase domain of PSD-95. According to Sala and Sheng (1999), with permission.

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. 

Kapp, K., Schubler, P., Kunz, W. and Grevelding, C.G. (2001) Identification, isolation and characterization of a Fyn-like tyrosine kinase from Schistosoma mansoni. Parasitology 1 22, 31 7-327. 

Mulhern, T. D., Shaw, G. L., Morton, C. J., Day, A. J., and Campbell, I. D. (1997). The SH2 domain from the tyrosine kinase Fyn in complex with a phosphotyrosyl peptide reveals insights into domain stability and binding specificity. Structure 5, 1313-1323. 

Ilangumaran, S., Ami, S., van Echten-Deckert, G., Borisch, B., and Hoessli, D. C. (1999). Microdomain-dependent regulation of Lck and Fyn protein-tyrosine kinases in T lymphocyte plasma membranes. Mol. Biol. Cell 10(4), 891-905. 

A more detailed picture of the folding of the SH3 (Src homology 3) domain of the Fyn protein kinase has been obtained by relaxation dispersion experiments.93 9 SFI3 domains bind proline-rich sequences and are key components of proteins involved in protein tyrosine kinase signalling pathways. The folding of the SFI3 domain of the Fyn protein kinase has been extensively characterized by stopped-flow and NMR experiments. CPMG relaxation dispersion analysis revealed that the Fyn SH3 domain is essentially a three-state folder with an intermediate state. 

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