Fyn in Neurodevelopment and Ischemic Brain Injury

Abstract

The Src family kinases (SFKs) are nonreceptor protein tyrosine kinases that are implicated in many normal and pathological processes in the nervous system. The SFKs Fyn, Src, Yes, Lyn, and Lck are expressed in the brain. This review will focus on Fyn, as Fyn mutant mice have striking phenotypes in the brain and Fyn has been shown to be involved in ischemic brain injury in adult rodents and, with our work, in neonatal animals. An understanding of Fyn's role in neurodevelopment and disease will allow researchers to target pathological pathways while preserving protective ones.

Figure 1

Structure of FynB A) Domain structure of FynB including N-terminal myristoylation (Myr) and palmitylation (Palm) sites as well as regulatory tyrosine residues. B) Fyn binding partners in the unique region (black), SH3 domain (red) and SH2 domain (orange). These are the partners that have been published with demonstrated interactions with specific SH2 or SH3 domain. MAG: myelin-associated glycoprotein; SAP-1: stomach cancer-associated protein-tyrosine phosphatase-1; TRPC-6: transient receptor potential channel member 6

Figure 2

Inactive and active conformations of Fyn Phosphorylation of Y531 in the C-terminus leads to intramolecular interactions that prevent kinase activity and protein-protein interactions, while phosphorylation of Y420 leads to an open structure that is catalytically active and accessible to binding partners.

Figure 3

Fyn complexes during ischemia in adult and neonatal rodents A) In response to ischemia in adult rodents, Fyn interacts with two receptors that flux calcium, the NMDA receptor and α1c subunit of L-type voltage gated calcium channel. PSD95 facilitates the interaction between Fyn and NR2A. Fyn also associates with SynGAP. Additionally, PSD93 interacts with NR2A/NR2B as well as with Fyn. Tyrosine-phosphorylated PSD93 binds to Csk, a negative regulator of SFKs. PSD93 enhances Fyn/NR2B association and NR2B tyrosine phosphorylation in adult brain ischemia. B) Fyn forms a complex with NMDA receptor subunits NR2A and NR2B during neonatal hypoxic-ischemic brain injury. These proteins are tyrosine phosphorylated by Fyn, which strengthens complex formation and likely contributes to pathogenic signaling in the setting of ischemia. C) Phosphorylation of Y1472 NR2B by Fyn mediates cell death by reactive oxygen species (ROS) generation in a calcium independent manner.