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An unrecognized extracellular function for an intracellular adapter protein released from the cytoplasm into the

Paul J Mintz1, Marina Cardó-Vila, Michael G Ozawa

  • 1University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

Proceedings of the National Academy of Sciences of the United States of America
|January 27, 2009
PubMed

Insights

Researchers discovered a novel interaction between the CRKL adapter protein and beta(1) integrin outside cells. This interaction promotes tumor growth, suggesting new therapeutic targets for cancer.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Biochemistry

Background:

  • Mammalian cell membranes regulate intracellular and extracellular environments.
  • Cytoplasmic signaling adapter proteins are not typically considered functional in the extracellular tumor milieu.
  • Integrins are crucial cell surface receptors involved in cell adhesion and signaling.

Purpose of the Study:

  • To investigate potential functional roles of cytoplasmic adapter proteins in the extracellular tumor environment.
  • To identify novel protein-protein interactions in the tumor microenvironment.
  • To explore the implications of these interactions for cancer development and potential therapeutic strategies.

Main Methods:

  • Utilized combinatorial random peptide libraries for selection in tumor-bearing mice.
  • Performed in vitro, in cellulo, and in vivo assays to validate interactions and functional consequences.
  • Employed biochemical and cell-based assays to analyze protein-protein interactions and signaling pathways.

Main Results:

  • Identified a direct, specific interaction between CRKL (an adapter protein with SH2 and SH3 domains) and the plexin-semaphorin-integrin domain of beta(1) integrin in the extracellular tumor environment.
  • Demonstrated that this interaction, involving an intracellular adapter acting extracellularly, triggers an alternative integrin-mediated signaling cascade.
  • Showed this cascade promotes cell growth and survival, contributing to tumorigenesis.

Conclusions:

  • The adapter protein CRKL interacts with beta(1) integrin extracellularly, challenging the conventional understanding of adapter protein function.
  • This unconventional interaction activates a novel signaling pathway promoting tumor cell proliferation and survival.
  • Secreted CRKL may function as a growth-promoting factor in tumorigenesis, representing a potential therapeutic target for cancer treatment.

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