Les protéines tyrosine kinases non récepteurs de la famille SRC dans le système nerveux central

Abstract

Les protéine-tyrosine kinases (PTK) de la famille de la p60c-Src (PTKSrc) ont été découvertes dans des tumeurs. Elles sont cependant synthétisées à un niveau très élevé dans des tissus où il n’y a pas de division cellulaire, comme les plaquettes ou le système nerveux central (forme neuronale de la p60c-Src). L’étude des PTKSrc dans le système nerveux central a permis de leur assigner deux grands rôles. Le premier concerne la différenciation ; il est mis en évidence par : (1) la localisation de la p60c-Src et de la p59Fyn dans les cônes de croissance ; (2) l’inhibition de la croissance des neurites sur support défini en l’absence de la p60c-Src ; (3) la modulation de la différenciation de lignées de neuroblastomes par transfection du gène codant pour la p60c-Src. Le second rôle, de découverte plus récente, est la phosphorylation de résidus tyrosines de récepteurs d’acides aminés excitateurs et de canaux ioniques, ce qui les met dans une situation idéale pour agir sur la plasticité synaptique.

The protein tyrosine kinases of the Src family (PTKSrc) are non-receptor tyrosine kinases. They share common structural features, are located in the cytoplasm and are associated to the plasma membrane. Several PTKSrc are expressed simultaneously in tissues. The survival, and apparent absence of defect in mice following the knock-out of the different PTKSrc, together with high homology and previous implication in several key cellular functions, raised the question of their possible redundancy. In the central nervous system (CNS), p60(c-Src), p62(Yes) and p59(Fyn) are highly expressed and one form (p60(c-Src+)) is specifically found. Various strategies have been used to analyze the specific role 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 Src(-/-) cells on a defined matrix. On the other hand, the knock-out of p50(CSK), a PTK that inactivates several (and possibly all) PTKSrc, was lethal, indicating that tight regulation of the PTKSrc is important. Depending on the intracellular context or the differentiation state of cells, activation of p60(c-Src) could result in a different cell response. indeed, overexpression of p60(c-Src) inhibited neuronal differentiation in the teratocarcinoma P19 and activated it in the PC12 pheochromocytoma. A role of PTKSrc in the nervous system was also indicated by the phosphorylation of excitatory amino acid receptors such as the NMDA and GABA(A) receptors, probably due to p60(c-Src). This points to a role of PTKSrc in synaptic plasticity, a role which was also suggested by the impairment of long term potentiation (LTP) in p59(Fyn) knock-out mice; although these mice have a severe development defect of the hippocampus. In conclusion, several PTKSrc are expressed at high level in the CNS; their function appears to be related to the differentiation process of neurons at two main levels: formation of interneuronal connections, and modulation of these connections (synaptic plasticity). [References: 39]