Dimerization of tyrosine phosphatase PTPRO decreases its activity and ability to inactivate TrkC

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Receptor-protein tyrosine phosphatases (RPTPs) are crucial for neuronal differentiation, similar to receptor tyrosine kinases.
• The dimerization mechanisms and activity regulation of RPTPs remain largely unexplored compared to receptor tyrosine kinases.

Purpose of the Study:

• To investigate the dimerization of the neuronal type III RPTP, PTPRO.
• To determine the impact of PTPRO dimerization on its phosphatase activity.

Main Methods:

• Examined PTPRO dimerization in living cells.
• Investigated the role of disulfide linkages in PTPRO dimerization.
• Utilized a chimeric fusion protein to induce dimerization of PTPRO's extracellular and intracellular domains.
• Assessed PTPRO activity against artificial peptides and tropomyosin-related kinase C (TrkC).

Main Results:

• PTPRO forms dimers in living cells, with disulfide linkages in its intracellular domain potentially regulating this process.
• Ligand-induced dimerization of PTPRO's extracellular and intracellular domains reduced its phosphatase activity.
• PTPRO efficiently dephosphorylated TrkC, a putative substrate, and both proteins co-precipitated from transfected cells.
• Inhibition of PTPRO activity by dimerization contrasts with increased activity observed in the related RPTP, CD148/PTPRJ.

Conclusions:

• PTPRO dimerization inhibits its phosphatase activity, suggesting a novel regulatory mechanism.
• The relationship between dimerization and activity in type III RPTPs is complex and may vary between family members.