Human CD38: a (r)evolutionary story of enzymes and receptors

Abstract

Human CD38 is the mammalian prototype of a family of proteins which share structural similarities and an ectoenzymatic activity involved in the production of calcium mobilizing compounds. Besides the enzymatic activity, the molecule performs as a receptor, ruling adhesion and signaling in leukocytes. These functions are exerted through the interaction with surface ligands, one of which was identified as CD31. Recently, CD38 has gained attention as a prognostic marker and a pathogenetic agent in leukemias and in other diseases. Together these insights have produced a model of an as yet unique family of molecules, which act independently as receptors and enzymes.

Introduction

Understanding the CD38 receptor system has been an unfolding odyssey which lasted over two decades. The current view of this receptor system results from combined observations from several laboratories and clinics working on different aspects of the molecule.

Human CD38 was initially defined by Reinherz and Schlossman in 1980 in their pioneering studies of thymocyte and T lymphocyte differentiation antigens [1]. Several monoclonal antibodies (mAbs) later raised against CD38 have been clustered since the Third International Workshop on Human Differentiation Antigens in 1987. The turning point in the study of the molecule was marked by the finding of a structural and functional similarity with a soluble enzyme purified from the mollusc Aplysia californica [2]. As a consequence, scientists of a biochemical bent focused their attention on the catalytic activities of CD38, while the immunologists adopted a new perspective from which to view the molecule as a surface receptor. The convergence of these two approaches will provide a unifying view of the biology and functions of CD38.

This laboratory stumbled across CD38, while raising mAbs against HLA Class II products [3]. The A10 mAb (and its subclone IB4, a hybridoma selected for its high antibody production) was used for an initial structural and functional analysis of the molecule [4], [5]. This mAb was also able to induce modulatory effects on the expression of surface activation markers in T, B, NK and plasma cells [6]. Additionally, A10 mAb induced proliferation in several cells analyzed and the phenomenon was accessory cell- and interleukin-(IL)-2-dependent. The effects induced by A10 mAb suggested that CD38 was involved in the activation of lymphoid and myeloid cells, although understanding of its mechanisms was murky at best. The finding of a physical and functional membrane association between CD38 and the main signaling complexes of T, B and NK cells [7] represented a step forward in defining the signals mediated by CD38. The resulting view was of CD38 as a promiscuous receptor, which took advantage of the machinery of dedicated signaling receptors. The presence of specialized compartments in the plasma membrane containing clusters of co-modulating structures, including different receptors involved in the transduction of extracellular signals, significantly supported this view [8], [9]. This scenario was further refined by the identification of a cell surface ligand for CD38 [10]. Thus, CD38 was ushered into the world of adhesion molecules, and was found to be involved in heterotypic cell interactions, both in open environments (e.g. T lymphocytes interacting with endothelial cells in blood vessels) [11] and in closed ones (e.g. immature hemopoietic cells interacting with stromal cells in the bone marrow and mature residential T and B cells).

While immunologists were busy defining its signals and ligands, biochemists concentrated on its enzymatic aspects and eventually revealed the complete range of catalytic functions of the molecule [12], [13], [14]. Even as an enzyme, CD38 may be considered promiscuous, as it apparently works in strict collaboration with a network of surface enzymes involved in the metabolism of NAD⁺ [15].

A final major contribution was made as a result of a thorough genetic analysis which began more than a decade ago. The gene coding for CD38 was assigned to chromosome 4 by using a conventional approach of somatic cell genetics (i.e. the OKT10 mAb was used to detect expression of CD38 on murine×human somatic hybrids) [16]. This work was completed a few years ago with the identification of a CD38 gene cluster which encodes a family of surface molecules. These CD38 family members share phylogenetic origins, structural conformation and biological functions [17](Fig. 1).