Blood Journal
Leading the way in experimental and clinical research in hematology

Murine natural killer immunoreceptors use distinct proximal signaling complexes to direct cell function

  1. Rebecca M. May1,
  2. Mariko Okumura1,
  3. Chin-Jung Hsu2,
  4. Hamid Bassiri3,
  5. Enjun Yang1,
  6. Gregory Rak3,
  7. Emily M. Mace3,
  8. Naomi H. Philip1,
  9. Weiguo Zhang4,
  10. Tobias Baumgart2,
  11. Jordan S. Orange3,
  12. Kim E. Nichols3, and
  13. Taku Kambayashi1,*
  1. 1 Div. of Transfusion Medicine and Therapeutic Pathology, Dept. of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States;
  2. 2 Department of Chemistry, University of Pennsylvania, Philadelphia, PA, United States;
  3. 3 Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States;
  4. 4 Department of Immunology, Duke University Medical Center, Durham, NC, United States
  1. * Corresponding author; email: taku.kambayashi{at}

Key points

  • Two distinct proximal signaling complexes are formed involving SLP-76 and LAT1/LAT2 or ADAP by immunoreceptor-activated NK cells.

  • Both signaling pathways formed by LAT1/LAT2 and ADAP with SLP-76 are required for the optimal function of immunoreceptor-activated NK cells.


Signaling pathways leading to natural killer (NK) cell effector function are complex and incompletely understood. Here, we investigated the proximal signaling pathways downstream of immunotyrosine-based activation motif (ITAM) bearing activating receptors. We found that the adaptor molecule SH2 domain-containing leukocyte protein of 76 kD (SLP-76) is recruited to microclusters at the plasma membrane in activated NK cells, and this is required for initiation of downstream signaling and multiple NK cell effector functions in vitro and in vivo. Surprisingly, we found that two types of proximal signaling complexes involving SLP-76 were formed. In addition to the canonical membrane complex formed between SLP-76 and linker for activation of T cells (LAT) family members, a novel LAT family-independent SLP-76-dependent signaling pathway was identified. The LAT family-independent pathway involved the SH2 domain of SLP-76 and adhesion and degranulation-promoting adaptor protein (ADAP). Both the LAT family-dependent and ADAP-dependent pathway contributed to IFNγ production and cytotoxicity, but was not essential for other SLP-76-dependent events including phosphorylation of AKT and extracellular signal related kinase and cellular proliferation. These results demonstrate that NK cells possess an unexpected bifurcation of proximal ITAM-mediated signaling, each involving SLP-76 and contributing to optimal NK cell function.

  • Submitted December 26, 2012.
  • Accepted February 3, 2013.