Function

Studies using CD45-deficient T and B cell lines demonstrate that CD45 is an obligate positive regulator of antigen receptor signaling. Ablation of the murine CD45 gene by three independent groups reveals its critical positive role in lymphocyte development and activation [2,9]. For example, thymocyte development is largely blocked and the few mature T cells produced are refractory to TCR stimulation. Loss of CD45 in humans results in a form of severe combined immunodeficiency (SCID) [2,9].

Src family kinases (SFKs) are a primary substrate for CD45. SFKs are responsible for initiating antigen receptor signaling. They also modulate signal transduction cascades

Figure 1 Structure of CD45. CD45 exists as multiple isoforms due to alternative splicing of three exons (4, 5, and 6, designated A, B, and C) in the extracellular domain. The largest isoform, RABC (including all three exons), and the smallest isoform, RO (lacking all three exons), are shown. These three exons encode multiple sites of O-linked glycosylation. As a result, various isoforms differ substantially in size, shape, and negative charge. The remaining extracellular domain is heavily N-glycosylated and contains a cysteine-rich region followed by three fibronectin type III repeats. CD45 has a single transmembrane domain and a large cytoplasmic tail containing two tandemly duplicated PTPase domains, D1 and D2. Only D1 has enzymatic activity and is necessary to rescue T-cell receptor (TCR) signaling in a CD45-deficient cell line. The function of D2 is currently unclear. In addition, molecular modeling indicates that the juxtamembrane region may form a structural wedge.

Figure 1 Structure of CD45. CD45 exists as multiple isoforms due to alternative splicing of three exons (4, 5, and 6, designated A, B, and C) in the extracellular domain. The largest isoform, RABC (including all three exons), and the smallest isoform, RO (lacking all three exons), are shown. These three exons encode multiple sites of O-linked glycosylation. As a result, various isoforms differ substantially in size, shape, and negative charge. The remaining extracellular domain is heavily N-glycosylated and contains a cysteine-rich region followed by three fibronectin type III repeats. CD45 has a single transmembrane domain and a large cytoplasmic tail containing two tandemly duplicated PTPase domains, D1 and D2. Only D1 has enzymatic activity and is necessary to rescue T-cell receptor (TCR) signaling in a CD45-deficient cell line. The function of D2 is currently unclear. In addition, molecular modeling indicates that the juxtamembrane region may form a structural wedge.

emanating from growth factors, cytokines, and integrin receptors [1,2,10]. In most CD45-deficient cells, SFKs are hyper-phosphorylated at the negative regulatory tyrosine [1,2]. Moreover, expression of a constitutively active Lck Y505F mutant in CD45-deficient mice largely rescues the block in T-cell development [11]. By preferentially dephosphorylat-ing the negative regulatory tyrosine, CD45 can maintain SFKs in a primed, or signal-competent, state capable of full activation upon receptor stimulation.

Although CD45 clearly plays a positive role in antigen receptor signaling, it can also function as a negative regulator in other settings. For example, CD45-deficient macrophages and T cells are abnormally adherent [12,13]. Despite hyper-phosphorylation of the negative regulatory tyrosine of the SFKs, kinase activity is enhanced due to hyperphosphoryla-tion at low stoichiometry of the autophosphorylation site, explaining the increased adhesiveness of these cells. This finding suggests that both the autophosphorylation site and the negative regulatory tyrosines can serve as CD45 substrates in some contexts. Interestingly, similar findings have been described for antigen receptor signaling in some CD45-deficient T and B cell lines [9,10]. The discrepancy of positive and negative effects of CD45 can be explained by its inclusion in or exclusion from clustered signaling complexes.

Physical separation from the TCR during antigen recognition at the immunological synapse results in a net positive effect, while access to its substrate during integrin-mediated adhesion results in a negative effect [10].

In addition to SFKs, CD45 may also negatively regulate cytokine- and interferon-receptor-mediated activation by dephosphorylating Janus tyrosine kinases (JAKs) [14]. Other possible, but controversial, substrates include ZAP-70 and CD3Z [2].

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