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Lnk adaptor protein down-regulates specific Kit-induced signaling pathways in primary mast cells

Clotilde Simon1, Elisabetta Dondi, Amandine Chaix

  • 1Institut Cochin, Université Paris Descartes, CNRS UMR8104, Paris, France.

Blood
|August 30, 2008
PubMed

Insights

The adaptor protein Lnk negatively regulates stem cell factor (SCF) signaling by binding to the Kit receptor. This binding inhibits hematopoietic cell proliferation and migration, clarifying Lnk

Area of Science:

  • Immunology
  • Cell Biology
  • Hematopoiesis

Background:

  • Stem cell factor (SCF) is crucial for hematopoietic progenitor and mast cell development via the Kit receptor.
  • The adaptor protein Lnk is recognized as a negative regulator of SCF signaling, but its precise mechanism remains elusive.

Purpose of the Study:

  • To elucidate the molecular mechanism by which Lnk negatively regulates SCF signaling.
  • To investigate Lnk's role in SCF-induced proliferation, migration, and hematopoietic progenitor expansion.

Main Methods:

  • Investigated the direct binding of Lnk's Src homology 2 (SH2) domain to phosphorylated tyrosine 567 in the Kit juxtamembrane domain.
  • Utilized Lnk-deficient bone marrow mast cells (BMMCs) reconstituted with various Lnk proteins.
  • Assessed SCF-induced proliferation, migration, mitogen-activated protein kinase (MAPK), c-jun N-terminal kinase (JNK), Rac, and p38 MAPK activation.

Main Results:

  • Lnk directly binds to phosphorylated tyrosine 567 of Kit, inhibiting SCF-induced proliferation and attenuating MAPK and JNK signaling.
  • Lnk deficiency enhances SCF-dependent migration, associated with increased Rac and p38 MAPK activation, indicating a novel inhibitory role.
  • Different Lnk domains and its carboxy-terminal tyrosine differentially affect the inhibition of hematopoietic progenitor expansion.

Conclusions:

  • Lnk acts as a negative modulator of SCF signaling by binding to Kit tyrosine 567.
  • This interaction specifically inhibits SCF-dependent pathways regulating hematopoietic cell proliferation and migration.
  • Lnk's regulatory function is critical for controlling the behavior of primary hematopoietic cells.

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