Adenosine deaminase-related growth factors stimulate cell proliferation in Drosophila by depleting extracellular adenosine

Abstract

We describe a protein family in Drosophila containing six adenosine deaminase-related growth factors (ADGFs), which are homologous to a mitogenic growth factor discovered in conditioned medium from cells of a different fly species, Sarcophaga. Closely related proteins have been identified in other animals, and a human homolog is implicated in the genetic disease Cat-Eye Syndrome. The two most abundantly expressed ADGFs in Drosophila larvae are ADGF-A, which is strongly expressed in the gut and lymph glands, and ADGF-D, which is mainly expressed in the fat body and brain. Recombinant ADGF-A and ADGF-D are active adenosine deaminases (ADAs), and they cause polarization and serum-independent proliferation of imaginal disk and embryonic cells in vitro. The enzymatic activity of these proteins is required for their mitogenic function, making them unique among growth factors. A culture medium prepared without adenosine, or depleted of adenosine by using bovine ADA, also stimulates proliferation of imaginal disk cells, and addition of adenosine to this medium inhibits proliferation. Thus ADGFs secreted in vivo may control tissue growth by modulating the level of extracellular adenosine.

Structural Basis for the Growth Factor Activity of Human Adenosine Deaminase ADA2

“…The ADGF/ADA2 family proteins (3,14,15) were first described as growth factors in insects (16,17) and later were found to possess the ADA activity, which was shown to be essential for the growth factor activity (3,18,19). The physiological role is best described for the Drosophila homologue, ADGF-A (3,20).…”

“…All three types of ADA are present in humans, where they are known as ADA1, ADA2, and ADA3 (2). In flies, ADGF/ADA2 is the only active adenosine deaminative enzyme (3), whereas in rodents, there is only a gene for ADA1 (2), suggesting that these proteins have overlapping functions but that the presence of the two in a given organism is beneficial for its survival.…”

“…Extracellular adenosine can bind and activate four adenosine receptors (ADRs), 3 A 1 , A 2A , A 2B , and A 3 , which are expressed in different combinations on the surface of almost all cell types, and the receptor activation triggers multiple intracellular processes either leading to cell activation or resulting in suppression of cell function and cell death (1).…”

Identification of iron-loaded ferritin as an essential mitogen for cell proliferation and postembryonic development in Drosophila

“…Recombinant ADGFs are active adenosine deaminases and stimulate serum-independent proliferation of Cl8 cells in vitro. It is believed that ADGFs secreted in vivo may control tissue growth by modulating the level of extracellular adenosine [12].…”

“…Two families of polypeptide growth factors, imaginal disc growth factors (IDGFs) [11] and adenosine deaminase-related growth factors (ADGFs) [12], have been reported to have stimulatory effects on Cl8 cell growth. IDGFs were purified from the conditioned medium of Cl8 cells as proteins that stimulate Cl8 cell growth in cooperation with insulin.…”