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

Blood. 2008 Nov 15;112(10):4039-47. doi: 10.1182/blood-2008-05-154849. Epub 2008 Aug 27.

Abstract

Stem cell factor (SCF) plays critical roles in proliferation, survival, migration, and function of hematopoietic progenitor and mast cells through binding to Kit receptor. Previous studies have implicated the adaptor protein Lnk as an important negative regulator of SCF signaling. However, the molecular mechanism underlying this regulation is unclear. Here, we showed that the Src homology 2 domain (SH2) of Lnk binds directly and preferentially to phosphorylated tyrosine 567 in Kit juxtamembrane domain. Using Lnk(-/-) bone marrow mast cells (BMMCs) transduced with different Lnk proteins, we demonstrated that Lnk down-regulates SCF-induced proliferation with attenuation of mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase signaling. Furthermore, we showed that Lnk(-/-) BMMCs displayed increased SCF-dependent migration compared with wild-type cells, revealing a novel Lnk-mediated inhibitory function. This correlated with enhanced Rac and p38 MAPK activation. Finally, we found that Lnk domains and carboxy-terminal tyrosine contribute differently to inhibition of in vitro expansion of hematopoietic progenitors. Altogether, our results demonstrate that Lnk, through its binding to Kit tyrosine 567, negatively modulates specific SCF-dependent signaling pathways involved in the proliferation and migration of primary hematopoietic cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism*
  • Cell Movement / physiology
  • Cell Proliferation
  • Cell Survival / physiology
  • Cells, Cultured
  • Down-Regulation / physiology
  • Enzyme Activation / physiology
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism
  • Intracellular Signaling Peptides and Proteins
  • MAP Kinase Signaling System / physiology*
  • Mast Cells / cytology
  • Mast Cells / metabolism*
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / metabolism*
  • Stem Cell Factor / genetics
  • Stem Cell Factor / metabolism*
  • Transduction, Genetic
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism
  • src Homology Domains

Substances

  • Adaptor Proteins, Signal Transducing
  • Intracellular Signaling Peptides and Proteins
  • Lnk protein, mouse
  • Membrane Proteins
  • Proteins
  • Stem Cell Factor
  • Proto-Oncogene Proteins c-kit
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases