Figure 3
From: Overcoming barriers and thresholds – signaling of oligomeric Aβ through the prion protein to Fyn
Fyn’s role as a signal integration hub involved in a number of cellular programs need to be taken into account when assessing role of PrP in oAβ excitotoxicity paradigms. (A) Fyn belongs to the family of non-receptor-type protein tyrosine kinases referred to as Src family kinases (SFKs), of which five members (Src, Fyn, Yes, Lck and Lyn) are known to be expressed in the human brain, and Fyn and Src are of primary interest in the context reviewed here [76]. All SFKs share a modular domain organization composed of a Src homology 2 (SH2) domain sandwiched between an N-terminal Src homology 3 (SH3) domain and a C-terminal tyrosine kinase domain. The inactive state of these kinases can be stabilized by an intramolecular interaction that forms when the SH2 domain binds to a C-terminal tyrosine-phosphate (Y527). Full activation requires dephosphorylation of this inhibitory phosphate and autophosphorylation within the activation loop in the tyrosine kinase domain. Various tyrosine kinases and phosphatases have been shown to control occupancy of these critical acceptor sites. Thus, SFK activity is negatively regulated through Y527 phosphorylation by C-terminal Src Kinase (CSK) or CSK homologous kinase (CHK) and through dephosphorylation of Y416 by striatal-enriched tyrosine phosphatase (STEP) [77]. Positive effectors of SFK activity are the receptor-type protein tyrosine phosphatases Shp-2 [78, 79] and PTPRA [35, 36] that were shown to selectively remove the inhibitory Y527 phosphate. (B) Cellular programs known to modulate Fyn activation levels. Upon oAβ binding to PrPC and signaling to Fyn, the cumulative Fyn activation level will be reflective of the cell type, its developmental status and the programs executed in the cell.