Tyrosine phosphorylation and association of BIT with SHP-2 induced by neurotrophins.
BIT (brain immunoglobulin-like molecule with tyrosine-based activation motifs) is a membrane glycoprotein that has two cytoplasmic TAMs (tyrosine-based activation motifs). We previously reported that tyrosine-phosphorylated TAMs of BIT interact with the Src homology 2 domain-containing protein tyrosine phosphatase SHP-2 both in vitro and in transfected cells, and this association results in a potent stimulation of the phosphatase activity of SHP-2. Both BIT and SHP-2 are highly expressed in the mammalian brain, and they may play important roles in the regulation of synaptic function. In this study, we found that nerve growth factor (NGF) treatment of PC12 cells leads to the tyrosine phosphorylation of BIT and a subsequent complex formation between BIT and SHP-2. Furthermore, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) also induced the tyrosine phosphorylation of BIT and the association with SHP-2 in primary cultured rat neurons. Our results suggest that the BIT-SHP-2 signaling pathway is a novel signal transduction mechanism of neurons that acts in response to neurotrophic factors such as NGF, BDNF, and NT-3.
Ohnishi
H
H
Mitsubishi Kasei Institute of Life Sciences, Machida, Tokyo, Japan.
Yamada
M
M
Kubota
M
M
Hatanaka
H
H
Sano
S
S
D000818:Animals; D000943:Antigens, Differentiation; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D020933:Neurotrophin 3; D016716:PC12 Cells; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism*
D000943:Antigens, Differentiation; D019208:Brain-Derived Neurotrophic Factor; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules; D020933:Neurotrophin 3; D011971:Receptors, Immunologic; D014443:Tyrosine; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516727:Ptpn11 protein, rat; C509250:Ptpn6 protein, rat