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Related Experiment Videos

Lefty proteins exhibit unique processing and activate the MAPK pathway.

L Ulloa1, J W Creemers, S Roy

  • 1Department of Pathology, Gene Therapy and Viral Vector Laboratory, North Shore-Long Island Jewish Health System and Biomedical Research Center, Manhasset, New York 11030, USA.

The Journal of Biological Chemistry
|March 30, 2001
PubMed
Summary

Lefty protein processing is crucial for embryonic development. Proprotein convertase 5A (PC5A) cleaves lefty into smaller forms, with the 28-kDa form and the precursor activating the MAPK pathway.

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Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Cell Signaling

Background:

  • Lefty polypeptides are novel transforming growth factor-beta (TGF-beta) superfamily members essential for embryonic lateral patterning.
  • Activation of TGF-beta superfamily members typically requires proteolytic processing, indicating cleavage is vital for lefty function.

Purpose of the Study:

  • To investigate the role of proprotein convertases (PCs) in lefty polypeptide processing.
  • To identify the specific PC enzymes involved in lefty cleavage.
  • To determine the biologically active form(s) of lefty and their signaling pathways.

Main Methods:

  • Transfection of cell lines with lefty and various PC enzymes.
  • Cotransfection analysis to assess PC activity on lefty precursor.

Related Experiment Videos

  • Site-directed mutagenesis to identify lefty cleavage sites.
  • Treatment of pluripotent P19 cells with different lefty forms to analyze cellular responses (Smad phosphorylation, MAPK activation).

    • Main Results:

    • PC5A was identified as the primary enzyme processing the lefty precursor to a 34-kDa form; other PCs showed limited activity.
    • Specific mutations in lefty (RGKR to GGKG and RHGR to GHGR) blocked processing to 34-kDa and 28-kDa forms, respectively.
    • The 28-kDa lefty form and the 42-kDa lefty precursor, but not the 34-kDa form, activated the MAPK pathway.
    • Lefty did not affect Smad2/Smad5 signaling pathways.

    Conclusions:

    • Lefty processing by PCs, particularly PC5A, is a key regulatory mechanism.
    • The 28-kDa form and the precursor itself are biologically active, signaling through the MAPK pathway.
    • Lefty processing regulates its biological activity and signaling, supporting a model of processing-dependent regulation.