George Shubinsky and Michael Schlesinger* expression of p190, a high-molecular-weight oligomeric form of CD38 (Umar et al., 1996). The short cytoplasmic The Paul Ehrlich Center for the Study of Normal and Leukemic WBC domain of CD38 contains no known motifs (Src homology domain 2 or 3 [SH2 or SH3], antigen receptor activa-The Hubert H. Humphrey Center for Experimental Medicine and Cancer Research tion [ARAM], or pleckstrin homology [PH]) that could mediate interactions with other signaling proteins and The Hebrew University—Hadassah Medical School Jerusalem 91120 seems to have no enzymatic activity. The cytoplasmic portion of both murine and rat CD38 contains one tyro-Israel sine residue that is not conserved in human CD38. The intracellular part of CD38 contains two conserved serine During the past two decades significant progress was residues within consensus sites recognized by cyclic made in understanding the molecular mechanisms of guanosine monophosphate (cGMP)–dependent protein intracellular signaling that control the growth and devel- kinases (Figure 1). cGMP-dependent serine/threonine opment of lymphocytes. Numerous cell surface recep- kinases in sea urchin eggs modulate the activity of ADP-tors were shown to trigger the phosphorylation of intra- ribosyl cyclase, an enzyme that displays a functional cellular proteins either via their intrinsic cytoplasmic homology to CD38 protein (Lund et al., 1996). The cytokinase domain or via associated intracellular protein ty- plasmic tail of CD38 might therefore serve as a regularosine kinases (PTKs). Protein phosphorylation plays a tory subunit of the CD38 ectoenzyme rather than as a key role in the initiation and propagation of various sig- tool for transduction of signals into the cell interior. naling cascades (Chan et al., 1994; Weiss and Littman, A number of CD38-related proteins, such as RT6, 1994; Kim et al., 1993a). The transmembrane signaling BST-1, and Yac-1, are GPI-anchored (Itoh et al., 1994; by surface receptors with ectoenzymatic activity and the Okazaki and Moss, 1996). In contrast, CD38 is a transmechanisms of their signaling function remain, however, membrane protein, and no GPI-anchored CD38 molepoorly understood. Regulatory signals may be gener- cules have been found on the cell surface. The transated by membrane-associated peptidases CD10/NEP, membrane domain of human CD38 includes 18 residues CD13/APN, CD26/DPPIV, and yBP-1. Glycosylphospha- of hydrophobic amino acids that are located between tidylinositol (GPI)–anchored ecto-5 nucleotidase (CD73), two short spacers that contain hydrophylic amino acids. which mediates lymphocyte-vascular adhesiveness, may Each of these spacers includes a triad of small amino also participate in the transduction of signals into the acids. It is noteworthy that analogous amino acid secell interior (Shipp and Look, 1993). quences determine GPI-cleavage/anchor sites and are A novel family of multifunctional membrane ectoen- found in the C terminus of primary translation products zymes has recently attracted attention. These ectoen- of all known GPI-anchored proteins (Englund, 1993). It zymes convert nicotinamide adenine dinucleotide (NAD) remains to be seen, therefore, whether this site is imporinto cyclic adenosine diphosphate ribose (cADP ribose), tant for any functional property of CD38 protein. hydrolyze cADP ribose to ADP ribose, and in addition Analysis of the extracellular part of CD38 indicates display NAD:(amino acid) protein–ADP-ribosyl trans- that it may function in attachment to the extracellular ferase activity. The CD38 surface protein is a member matrix …