Angiopoietins, Angiopoietin-like Proteins, and Receptors

Angiopoietins, Ang-1, Ang-2, and Ang-3 (mouse)/Ang-4 (human), are natural ligands of the Tie-2 receptor tyrosine kinase, which is expressed primarily on endothelial cells and early hematopoietic cells. These proteins are important modulators of angiogenesis and maintenance of vascular integrity. Tie-1 may also act as an angiopoietin receptor, possibly in complex with Tie-2. Two domains characterize the angiopoietin family of proteins: an N-terminal coiled-coil domain that mediates homo-oligomerization, and a C-terminal fibrinogen-like domain that binds Tie-2. Angiopoietin/Tie receptor signaling cascades are involved in fundamental angiogenesis events including vascular stabilization and remodeling, as well as recruitment of pericytes and smooth muscle cells. In addition, since an adequate blood supply is required for tumor growth, Angiopoietin/Tie receptor signaling is believed to play an important role in many cancer pathologies. Leukocyte Immunoglogulin-like Receptors (LILRs), also called CD85 or Immunoglobulin-like Transcripts (ILTs), have recently been described as receptors for several Angiopoietin-like proteins. LILRs comprise a family of immunomodulatory molecules that are expressed on professional antigen presenting cells. LILRs interact with self-proteins to provide inhibitory modulation of dendritic cells and down regulate their capacity to elicit T cell responses. Oligomerization of Angiopoietin-like proteins via the N-terminal coiled-coil domain is required to trigger LILR signaling. The Angiopoietin-like 2-LILRB2 interaction is involved in the expansion of hematopoietic stem cells. Additional Angiopoietin-like proteins interact with various members of the LILR family to promote regulation of innate immunity.