PROTEIN-TYROSINE KINASES OF THE SRC FAMILY IN THE CENTRAL-NERVOUS-SYSTEM

The protein tyrosine kinases of the Src family (PTKSrc) are non-recept or tyrosine kinases. They share common structural features, are locate d in the cytoplasm and are associated to the plasma membrane. Several PTKSrc are expressed simultaneously in tissues. The survival, and appa rent absence of defect in mice following the knock-out of the differen t PTKSrc, together with high homology and previous implication in seve ral kev cellular functions, raised the question of their possible redu ndancy. In the central nervous system (CNS), p60(c-Src), p62(Yes) and p59(Fyn) are highly expressed and one form (p60(c-Src+)) is specifical ly found. Various strategies have been used to analyze the specific ro le of PTKsrc in the CNS. Analysis of their subcellular distribution in neurons showed that they are abundant in dendrites, axons and growth cones. At the cellular level, the knock-outs allowed to detect subtle defects such as the impairment of neurite outgrowth of Srr(-/-) cells on a defined matrix. On the other hand, the knock-out of p50(CSK), a P TK that inactivates several (and possibly all) PTKSrc. was lethal, ind icating that tight regulation of the PTKSrc is important. Depending on the intracellular context or the differentiation state of cells, acti vation of p60(c-Src) could result in a different cell response. indeed , overexpression of p60(c-Src) inhibited neuronal differentiation in t he teratocarcinoma P19 and activated it in the PC12 pheochromocytoma. A role of PTKSrc in the nervous system was also indicated by the phosp horylation of excitatory amino acid receptors such as the NMDA and GAB A(A) receptors, probably due to p60(c-Src). This points to a role of P TKSrc in synaptic plasticity, a role which was also suggested by the i mpairment of long term potentiation (LTP) in p59(Fyn) knock-out mice; although these mice have a severe developmental defect of the hippocam pus. In conclusion, several PTKSrc are expressed at high level in the CNS; their function appears to be related to the differentiation proce ss of neurons at two main levels: formation of interneuronal connectio ns, and modulation of these connections (synaptic plasticity).