Fyn kinase

Also related to Src kinase structural biology have been studies on two SFKs, namely Lck and Fyn. Importantly, the X-ray structure of Lck kinase was the first SFK determined [64] as complexes with AMP-PNP, staurosporine and PP2. Furthermore, a Fyn kinase-staurosporine complex has been recently described [65]. Extrapolating from the above Src kinase inhibitor crystal structures with respect to the hydrophobic specificity pocket and the active conformation of the protein to bind ATP-competitive inhibitors of varying templates and functional group elaboration, a working hypothesis of known Src kinase inhibitors (vide infra) can be suggested (Fig. 4). 

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. 

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. 

Jain AK, Jaiswal AK. 2007. GSK-3beta acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2. J Biol Chem 282 16502-16510. 

Coyne, C.B., and Bergelson, J.M. (2006). Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions. Cell 124,119-131. 

Fyn kinase is a nonreceptor-type tyrosine kinase that has been proposed to act as a signaling molecule downstream of MAG. MAG and Fyn are coexpressed in oligodendrocytes, and can be coimmunoprecipited by biochemical methods. Fyn-null mice show an important reduction (about 50%) of CNS myelin, whereas myelination is quite normal in the MAG-null mice (see above). Double-deficient mice present a massive hypomyelination, associated with behavioral deficits. These data indicate the importance of both molecules in the initiation of myelination however, they could also mean that MAG and Fyn act in concert or independently in initiating myelination (Biffiger et al., 2000). 

Chin J, Palop JJ, Puolivali J et al (2005) Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer s disease. J Neurosci 25 9694-9703... 

Recently, a signal transduction activity of the prion protein by achieving tyrosine kinase Fyn was described (Mouillet-Richard et al, 2000). Since PrpC locates GPI-anchored at the cell surface, whereas Fyn-kinase is associated with the inner plasma membrane of the cell, a transmembrane receptor might mediate the PrP dependent activation of the Fyn-kinase. 

Arold, S., Franken, E, Strub, M. E, Hoh, F., Benichou, S., Benarous, R., and Dumas, C. (1997). The crystal structure of HIV-1 Nef protein bound to the Fyn kinase SH3 domain suggests a role for this complex in altered T cell receptor signaling. Structure 5, 1361-1372. 

Kinsey WH. 1996. Biphasic activation of Fyn kinase upon fertilization of the sea urchin egg. Dev Biol 174(2) 281-287. 

Levi M, Maro B, Shalgi R. 2010. Fyn kinase is involved in cleavage furrow ingression during meiosis and mitosis. Reproduction 140(6) 827-834. 

Luo J, McGinnis LK, Kinsey WH. 2009. Fyn kinase activity is required for normal organization and functional polarity of the mouse oocyte cortex. Mol Reprod Dev 76(9) 819-831. 

McGinnis LK, Kinsey WH, Albertini DF. 2009. Functions of Fyn kinase in the completion of meiosis in mouse oocytes. Dev Biol 327(2) 280-287. 

Rongish BJ, Kinsey WH. 2000. Transient nuclear localization of Fyn kinase during development in zebrafish. Anat Rec 260(2) 115-123. 

Talmor-Cohen A, Tomashov-Matar R, Tsai WB, Kinsey WH, Shalgi R. 2004b. Fyn kinase-tubulin interaction during meiosis of rat eggs. Reproduction 128(4) 387-393. 

Wu W, Kinsey WH. 2002. Role of PTPaseJs) in regulating Fyn kinase at fertilization of the... 

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