Src Family Kinases Control Neural Development and Function

Yagi, Takeshi

doi:10.1111/j.1440-169x.1994.00543.x

Cited by 18 publications

(1 citation statement)

References 43 publications

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“…Therefore, direct activation of SH-PTP2 by tyrosine-phosphorylated BIT-TAMs could induce activation of Src or other Src family kinases. The mammalian brain contains high levels of Src family protein-tyrosine kinases and recent observations have suggested that a Src family kinase, Fyn, functions in development of neural cells, modulation of longterm potentiation and regulation of behavior (44,45). The idea that Src family kinases may be involved in BIT regulation, is supported by our observation that recombinant GST-BIT fusion protein was tyrosine-phosphorylated by immunoprecipitated rat brain Src and Fyn in vitro (data not shown).…”

Section: Discussionsupporting

confidence: 66%

Activation of Protein-tyrosine Phosphatase SH-PTP2 by a Tyrosine-based Activation Motif of a Novel Brain Molecule

Ohnishi

Kubota

Ohtake

et al. 1996

Journal of Biological Chemistry

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BIT (a brain immunoglobulin-like molecule with tyrosine-based activation motifs) is a brain-specific membrane protein which has two cytoplasmic TAMs (tyrosine-based activation motifs). Using the Far Western blotting technique, we detected association of a 70-kDa protein with the tyrosine-phosphorylated TAMs of BIT. A mouse brain cDNA library in gt11 was screened for this association, and two positive clones encoding tyrosine phosphatase SH-PTP2 were isolated. SH-PTP2 has two SH2 domains and is believed to function as a positive mediator in receptor tyrosine kinase signaling. SH-PTP2 and BIT were coimmunoprecipitated from phosphorylated rat brain lysate, and BIT was a major tyrosine-phosphorylated protein associated with SH-PTP2 in this lysate. This interaction was also observed in Jurkat T cells transfected with BIT cDNA depending on tyrosine phosphorylation of BIT. Bisphosphotyrosyl peptides corresponding to BIT-TAMs stimulated SH-PTP2 activity 33-35-fold in vitro, indicating that two SH2 domains of SH-PTP2 simultaneously interact with two phosphotyrosines of BIT-TAM. Our findings suggest that the tyrosine phosphorylation of BIT results in stimulation of the signal transduction pathway promoted by SH-PTP2 and that BIT is probably a major receptor molecule in the brain located just upstream of SH-PTP2.Protein tyrosine phosphorylation plays an important role in signal transduction and regulates a wide range of cellular processes. Protein-tyrosine kinases and protein-tyrosine phosphatases are highly expressed in the central nervous system, consistent with the importance of tyrosine phosphorylation in neural function (1).BIT 1 (a brain immunoglobulin-like molecule with tyrosinebased activation motifs) is a novel immune antigen receptorlike molecule of the brain.2 This molecule is composed of an antigen receptor-like extracellular domain, a transmembrane domain, and a cytoplasmic region containing two variants of TAM (tyrosine-based activation motif) that was recently designated ITAM (immunoreceptor TAM). This cytoplasmic motif contains two tyrosine phosphorylation sites. TAM was originally described in the immune system where it plays a crucial role in the activation responses of B and T cells (2-5). BIT is one of major substrates of protein-tyrosine kinase(s) in crude brain suspensions 2 and is widely distributed in the brain in synapse-rich regions and in some nerve fibers.3 These findings suggest that the tyrosine phosphorylation of TAMs in BIT may be involved in neural signal transduction. Recent studies in the immune system have demonstrated that the oligomerization of TAMs allows the phosphorylation of two tyrosine residues found in this motif and these phosphotyrosine residues act as a bidentate docking site for the paired Src homology 2 (SH2) domains present in the cytoplasmic tyrosine kinases, Syk and ZAP-70, believed to be indispensable for initiation of the signaling cascade (6 -8). From these investigations, we predicted that TAMs of BIT may recruit tyrosine kinases containing paired SH2 domains to the ...

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Section: Discussionsupporting

confidence: 66%

Activation of Protein-tyrosine Phosphatase SH-PTP2 by a Tyrosine-based Activation Motif of a Novel Brain Molecule

Ohnishi

Kubota

Ohtake

et al. 1996

Journal of Biological Chemistry

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Wild-type and mutant forms ofv-src differentially alter neuronal migration and differentiation in vivo

Morgan

Majors

Galileo

2000

Journal of Neuroscience Research

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The effects of three different forms of v-src on brain cell development were determined in vivo. Recombinant retroviral vectors encoding the marker lacZ (control) and either wild-type v-src or SH2 or SH3 domain-deleted forms of v-src (deltaSH2 or deltaSH3, respectively) were used to infect neuronal progenitor cells in the embryonic chicken midbrain (optic tectum; OT). Embryos were injected in the OT with retroviral concentrates on embryonic day (E) 3 and sacrificed at E6, E9, and later in development. Patterns of cell proliferation, migration, and differentiation of lacZ-marked clonal cell progeny were then analyzed. Relative to lacZ-only controls, cell clone size at E6 was significantly increased for v-src-, unchanged for deltaSH2-, and smaller for deltaSH3-injected embryos. At E9, deltaSH2 cell clones were significantly larger than controls, suggesting increased survival from normal programmed cell death. Radial neuronal migration was impaired for v-src and deltaSH3 clones, whereas tangential neuronal migration was enhanced along fiber tracts in v-src and deltaSH2 clones. Moreover, radial glial cell development and differentiation was hindered in v-src and deltaSH3 clones. These experiments demonstrate that ectopic v-src signaling alters proliferation, migration, survival, and differentiation of developing brain cells and suggest that src signaling pathways are involved in these developmental processes. Furthermore, certain effects of v-src on brain cells require specific src homology domains.

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The Upregulation of NR2A-Containing N-Methyl-d-Aspartate Receptor Function by Tyrosine Phosphorylation of Postsynaptic Density 95 Via Facilitating Src/Proline-Rich Tyrosine Kinase 2 Activation

Zhao

Peng

et al. 2014

Mol Neurobiol

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The activation of postsynaptic N-methyl-D-aspartate (NMDA) receptors is required for long-term potentiation (LTP) of synaptic transmission. Postsynaptic density 95 (PSD-95) serves as a scaffold protein that tethers NMDA receptor subunits, kinases, and signal molecules. Our previous study proves that PSD-95 is a substrate of Src/Fyn and identifies Y523 on PSD-95 as a principal phosphorylation site. In this paper, we try to define an involvement and molecular consequences of PSD-95 phosphorylation by Src in NMDA receptor regulation. We found that either NMDA or chemical LTP induction leads to rapid phosphorylation of PSD-95 by Src in cultured cortical neurons. The phosphorylation of Y523 on PSD-95 potentiates NR2A-containing NMDA receptor current amplitude, implying an important role of Src-mediated PSD-95 phosphorylation in NMDA receptor activation. Comparing to wild-type PSD-95, overexpression of nonphosphorylatable mutant PSD-95Y523F attenuated the NMDA-stimulated NR2A tyrosine phosphorylation that enhances electrophysiological responses of NMDA receptor channels, while did not affect the membrane localization of NR2A subunits. PSD-95Y523D, a phosphomimetic mutant of PSD-95, induced NR2A tyrosine phosphorylation even if there was no NMDA treatment. In addition, the deficiency of Y523 phosphorylation on PSD-95 impaired the facilitatory effect of PSD-95 on the activation of Src and proline-rich tyrosine kinase 2 (Pyk2) and decreased the binding of Pyk2 with PSD-95. These results indicate that PSD-95 phosphorylation by Src facilitates the integration of Pyk2 to PSD-95 signal complex, the activation of Pyk2/Src, as well as the subsequent tyrosine phosphorylation of NR2A, which ultimately results in the upregulation of NMDA receptor function and synaptic transmission.

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Src Family Kinases Control Neural Development and Function

Cited by 18 publications

References 43 publications

Activation of Protein-tyrosine Phosphatase SH-PTP2 by a Tyrosine-based Activation Motif of a Novel Brain Molecule

Activation of Protein-tyrosine Phosphatase SH-PTP2 by a Tyrosine-based Activation Motif of a Novel Brain Molecule

Wild-type and mutant forms ofv-src differentially alter neuronal migration and differentiation in vivo

The Upregulation of NR2A-Containing N-Methyl-d-Aspartate Receptor Function by Tyrosine Phosphorylation of Postsynaptic Density 95 Via Facilitating Src/Proline-Rich Tyrosine Kinase 2 Activation

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