CD3ε recruits Numb to promote TCR degradation

Abstract

Modulation of TCR signaling upon ligand binding is achieved by changes in the equilibrium between TCR degradation, recycling and synthesis; surprisingly, the molecular mechanism of such an important process is not fully understood. Here, we describe the role of a new player in the mediation of TCR degradation: the endocytic adaptor Numb. Our data show that Numb inhibition leads to abnormal intracellular distribution and defective TCR degradation in mature T lymphocytes. In addition, we find that Numb simultaneously binds to both Cbl and a site within CD3ε that overlaps with the Nck binding site. As a result, Cbl couples specifically to the CD3ε chain to mediate TCR degradation. The present study unveils a novel role of Numb that lies at the heart of TCR signaling initiation and termination.

Selected signalling proteins recruited to the T‐cell receptor–CD3 complex

“…Constitutive expression of CD69 and interferon‐ γ , as well as constitutively phosphorylated ERK, are found in the CD4 + T cells from dominant negative Numb transgenic mice. Upon stimulation, CD4 + T cells from these mice exhibit higher ERK, ZAP‐70 and Akt phosphorylation than those of the wild‐type mice, indicating that Numb may be required for a negative control of TCR‐mediated signal transduction . It was suggested that Numb plays a role in TCR degradation by simultaneously binding to both Cbl and a site within CD3 ε that overlaps with the Nck binding site, thus mediating TCR degradation …”

“…Upon stimulation, CD4 + T cells from these mice exhibit higher ERK, ZAP-70 and Akt phosphorylation than those of the wild-type mice, indicating that Numb may be required for a negative control of TCR-mediated signal transduction. 84 It was suggested that Numb plays a role in TCR degradation by simultaneously binding to both Cbl and a site within CD3e that overlaps with the Nck binding site, thus mediating TCR degradation. 84 Numb can bind with its phosphotyrosine binding domain to the cytoplasmic tail of CD3e within the PRS to the sequence NPDY.…”

“…84 It was suggested that Numb plays a role in TCR degradation by simultaneously binding to both Cbl and a site within CD3e that overlaps with the Nck binding site, thus mediating TCR degradation. 84 Numb can bind with its phosphotyrosine binding domain to the cytoplasmic tail of CD3e within the PRS to the sequence NPDY. 84 Indeed, an endocytosis motif in CD3e in this region has been identified, 85 suggesting that Numb might be involved in TCR-CD3 endocytosis.…”

“…84 Numb can bind with its phosphotyrosine binding domain to the cytoplasmic tail of CD3e within the PRS to the sequence NPDY. 84 Indeed, an endocytosis motif in CD3e in this region has been identified, 85 suggesting that Numb might be involved in TCR-CD3 endocytosis. Interestingly, Numb was suggested to constitutively associate with CD3e.…”

Malignant tumor purity reveals the correlation between CD3E and low grade glioma microenvironment

“…TCR-CD3 complex assembly is initiated by forming two heterodimers CD3D/CD3E and CD3G/CD3E. It also participates in the internalization of TCR-CD3 complexes and cell surface down-regulation by endocytic sequences present in the cytoplasmic region of CD3E [40][41][42]. The relationship between the abundance of tumor in ltrating lymphocytes and the expression, copy number, methylation or mutation of CD3E in LGG was shown in Supplement Fig.…”