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Alternative splicing of ADAM15 regulates its interactions with cellular SH3 proteins

Iivari Kleino1, Rebekka M Ortiz, Miljamartta Yritys

  • 1Department of Virology, Haartman Institute, Helsinki University Central Hospital, University of Helsinki and HUSLAB, Haartmaninkatu 3, P.O. Box 21, FIN-00014 Helsinki, Finland.

Journal of Cellular Biochemistry
|September 1, 2009
PubMed

Insights

Alternative splicing of ADAM15 (A Disintegrin And Metalloprotease 15) isoforms dictates interactions with cellular partners like nephrocystin and SNX33. This splicing mechanism regulates ADAM15 functions, potentially explaining its varied roles in cancer.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • A Disintegrin And Metalloprotease (ADAM15) is linked to cancer, potentially through cadherin shedding.
  • Alternative mRNA splicing creates diverse ADAM15 isoforms with distinct cytosolic tail features.

Purpose of the Study:

  • To comprehensively characterize the Src homology-3 (SH3) domain binding potential of different ADAM15 isoforms.
  • To investigate how alternative splicing influences ADAM15 interactions with cellular partner proteins.

Main Methods:

  • Co-precipitation assays to identify binding partners.
  • Analysis of ADAM15 isoforms and their specific exon usage.
  • Identification of key amino acid residues for protein binding.

Main Results:

  • Alternative splicing significantly alters SH3-binding protein selection for ADAM15.
  • Nephrocystin specifically binds to ADAM15 isoforms i4, i5, and i6 via RxLPxxP motifs in exons 20/21.
  • Sorting nexin-33 (SNX33) associates with ADAM15 isoforms containing a specific carboxyterminal proline cluster.

Conclusions:

  • Alternative mRNA splicing is a key regulatory mechanism for ADAM15 intracellular protein interactions.
  • Differential protein binding by ADAM15 isoforms may explain their varied associations with cancer.

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