Fusion of PDGF receptor β to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation

Apoptosis is fundamental to the development and maintenance of animal tissues and the immune system1. Rapid clearance of apoptotic cells by macrophages is important to inhibit inflammation and autoimmune responses against intracellular antigens2,3,4. Here we report a new function for Mer, a member of the Axl/Mer/Tyro3 receptor tyrosine kinase family. merkd mice with a cytoplasmic truncation of Mer had macrophages deficient in the clearance of apoptotic thymocytes. This was corrected in chimaeric mice reconstituted with bone marrow from wild-type animals. Primary macrophages isolated from merkd mice showed that the phagocytic deficiency was restricted to apoptotic cells and was independent of Fc receptor-mediated phagocytosis or ingestion of other particles. The inability to clear apoptotic cells adequately may be linked to an increased number of nuclear autoantibodies in merkd mice. Thus, the Mer receptor tyrosine kinase seems to be critical for the engulfment and efficient clearance of apoptotic cells. This has implications for inflammation and autoimmune diseases such as systemic lupus erythematosus.

Phagocytosis and clearance of apoptotic cells is mediated by MER.

Neurotrophin receptors: a window into neuronal differentiation.

Recent studies have revealed that the TAM receptor protein tyrosine kinases — TYRO3, AXL and MER — have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.

Immunobiology of the TAM receptors

The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases

Using a sensitive transfection-tumorigenicity assay, we have isolated a novel transforming gene from the DNA of two patients with chronic myelogenous leukemia. Sequence analysis indicates that the product of this gene, axl, is a receptor tyrosine kinase. Overexpression of axl cDNA in NIH 3T3 cells induces neoplastic transformation with the concomitant appearance of a 140-kDa axl tyrosine-phosphorylated protein. Expression of axl cDNA in the baculovirus system results in the expression of the appropriate recombinant protein that is recognized by antiphosphotyrosine antibodies, confirming that the axl protein is a tyrosine kinase. The juxtaposition of fibronectin type III and immunoglobulinlike repeats in the extracellular domain, as well as distinct amino acid sequences in the kinase domain, indicate that the axl protein represents a novel subclass of receptor tyrosine kinases.

J P O'Bryan

Papers

axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase.