The B Cell Coreceptor CD22 Associates with AP50, a Clathrin-Coated Pit Adapter Protein, Via Tyrosine-Dependent Interaction

John, BinuJoy; Herrin, Brantley R.; Raman, Chander; Wang, Yanni; Bobbitt, Kevin; Brody, Brian A.; Justement, Louis B.

doi:10.4049/jimmunol.170.7.3534

Cited by 47 publications

(55 citation statements)

References 53 publications

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“…Antibody-mediated internalization of CD22 is dependent on its physical interaction with the clathrin-associated AP-2 adapter complex via tyrosinebased specific internalization motifs within its cytoplasmic domain (59,60). Tyr 843 or Tyr 863 and surrounding amino acids in the cytoplasmic tail of CD22 comprise the primary binding site for the AP50 subunit of AP-2 (60,61). Therefore, indiscriminate use of anti-CD22 fusion toxins and immunoconjugates would not offer an effective treatment opportunity for BPL with CD22ΔE12 lacking the internalization motifs required for their antileukemic action.…”

Section: Resultsmentioning

confidence: 99%

CD22 EXON 12 deletion as a pathogenic mechanism of human B-precursor leukemia

Uckun

Goodman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Here, we report that primary leukemic cells from infants with newly diagnosed B-precursor leukemia express a truncated and functionally defective CD22 coreceptor protein that is unable to transmit apoptotic signals because it lacks most of the intracellular domain, including the key regulatory signal transduction elements and all of the cytoplasmic tyrosine residues. Expression of this structurally and functionally abnormal CD22 protein is associated with a very aggressive in vivo growth of patients' primary leukemia cells causing disseminated overt leukemia in SCID mice. The abnormal CD22 coreceptor is encoded by a profoundly aberrant mRNA arising from a splicing defect that causes the deletion of exon 12 (c.2208-c.2327) (CD22ΔE12) and results in a truncating frameshift mutation. The splicing defect is associated with multiple homozygous mutations within a 132-bp segment of the intronic sequence between exons 12 and 13. These mutations cause marked changes in the predicted secondary structures of the mutant CD22 pre-mRNA sequences that affect the target motifs for the splicing factors hnRNP-L, PTB, and PCBP that are up-regulated in infant leukemia cells. Forced expression of the mutant CD22ΔE12 protein in transgenic mice perturbs B-cell development, as evidenced by B-precursor/B-cell hyperplasia, and corrupts the regulation of gene expression, causing reduced expression levels of several genes with a tumor suppressor function. We further show that CD22ΔE12-associated unique gene expression signature is a discriminating feature of newly diagnosed infant leukemia patients. These striking findings implicate CD22ΔE12 as a previously undescribed pathogenic mechanism in human B-precursor leukemia.

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Section: Resultsmentioning

confidence: 99%

CD22 EXON 12 deletion as a pathogenic mechanism of human B-precursor leukemia

Uckun

Goodman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Which of these functions is most prominent in wild-type NPC1 remains to be determined, but because of the inability of CD32-TM3 to be retained in late endosomes, it seems most likely that the primary function of transmembrane domain 3 is to redirect NPC1 mislocalized to the plasma membrane back into the endocytic system and that other signals within NPC1 are more important for late endosome retention of the protein. Tyrosinebased signals of the type YXX⌽ are able to act as plasma membrane internalization signals as well as direct endosomal targeting signals (41)(42)(43)(44)(45). These motifs are generally found in the cytoplasmic portion of proteins however, where they are recognized and bound by adapter proteins of the types already discussed.…”

Section: Discussionmentioning

confidence: 99%

Targeting of NPC1 to Late Endosomes Involves Multiple Signals, Including One Residing within the Putative Sterol-sensing Domain

Scott

Higgins

Davies

et al. 2004

Journal of Biological Chemistry

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The NPC1 protein is a multipass transmembrane protein whose deficiency causes the autosomal recessive lipid storage disorder Niemann-Pick type C1. NPC1 localizes predominantly to late endosomes and has a dileucine motif located within a small cytoplasmic tail thought to target the protein to this location. Our data have suggested previously that the protein can reach its correct location in the absence of its cytoplasmic tail, suggesting that other signals contribute to NPC1 targeting. By using various FLAG-tagged and CD32-NPC1 chimeric fusion constructs, we show that multiple signals are responsible for the trafficking of NPC1 to the endosomal compartment, including the dileucine motif and a previously unidentified signal residing within the putative sterol-sensing domain transmembrane domain 3. Neither region alone was capable of directing heterologous CD32 fusions to late endosomes exclusively via the trans-Golgi network to the late endosome route taken by wild-type NPC1; transmembrane domain 3 was unable to maintain CD32 in late endosomes, indicating that two or more signals work in concert to target and retain NPC1 in this compartment. In addition we confirm that the tail dileucine motif is not essential for NPC1 targeting to late endosomes, and we discuss the implications of this finding along with the previously unappreciated role for transmembrane domain 3 in NPC1 localization and function.

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“…More recently, however, sialoadhesin was found to be masked on splenic macrophages and largely unmasked on lymph node macrophages, suggesting that the degree of masking depends on the differential expression of cis ligands on the cell (18). These findings have generally been interpreted to mean that masking of siglecs by endogenous cis glycoprotein ligands can regulate the extent to which they are functionally available to interact with ligands on other cells in trans (17,18,20,(25)(26)(27).Cis ligands appear to be important modulators of the activity of CD22 as a regulator of B cell signaling. Indeed, inhibition of CD22 binding to cis ligands by using small molecule ligand mimics (14) or abrogation of its binding by site directed mutagenesis results in decreased SH2 domain-containing phosphatase 1 (SHP-1) recruitment and increased calcium flux after B cell receptor (BCR) crosslinking in vitro (15).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact

Collins

Blixt

DeSieno

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

160

134

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CD22, a negative regulator of B cell signaling, is a member of the siglec family that binds to ␣2-6-linked sialic acids on glycoproteins. Previous reports demonstrated that binding of multivalent sialoside probes to CD22 is blocked, or ''masked,'' by endogenous (cis) ligands, unless they are first destroyed by sialidase treatment. These results suggest that cis ligands on B cells make CD22 functionally unavailable for binding to ligands in trans. Through immunofluorescence microscopy, however, we observed that CD22 on resting B cells redistributes to the site of contact with other B or T lymphocytes. Redistribution is mediated by interaction with trans ligands on the opposing cell because it does not occur with ligand-deficient lymphocytes from ST6GalI-null mice. Surprisingly, CD45, proposed as both a cis and trans ligand of CD22, was not required for redistribution to sites of cell contact, given that redistribution of CD22 was independent of CD45 and was observed with lymphocytes from CD45-deficient mice. Furthermore, CD45 is not required for CD22 masking as similar levels of masking were observed in the WT and null mice. Comparison of the widely used sialoside-polyacrylamide probe with a sialoside-streptavidin probe revealed that the latter bound a subset of B cells without sialidase treatment, suggesting that cis ligands differentially impacted the binding of these two probes in trans. The combined results suggest that equilibrium binding to cis ligands does not preclude binding of CD22 to ligands in trans, and allows for its redistribution to sites of contact between lymphocytes. C D22 (Siglec-2) is a well-known regulator of B cell signaling (1-3), an activity mediated through its recruitment of SH2 domain-containing phosphatase 1 (also known as SHP-1) to the B cell receptor by immunoreceptor tyrosine-based inhibition motifs in its cytoplasmic domain (4, 5). The siglecs are a subgroup of the Ig superfamily that have in common a NH 2 -terminal Ig domain that binds sialic acid containing carbohydrates of glycoproteins as a ligand. CD22 is unique among the siglecs for its high specificity for sialoside ligands containing the sequence Sia␣2-6Gal that often terminates N-linked carbohydrate groups of glycoproteins (6, 7). The Sia␣2-6Gal sequence recognized by CD22 is differentially expressed in a cell typespecific manner (8-10) and is abundant on B and T lymphocytes (11,12). Several reports have suggested that the ligand-binding domain of CD22 can modulate its activity as a regulator of B cell signaling (5,(13)(14)(15). Although the precise ligand interactions that modulate CD22 function are not well understood, both cis (B cell) and trans (opposing cell) glycoprotein ligands appear to be important.CD22 is well documented to bind to endogenous B cell glycoproteins in cis. As elegantly demonstrated by Razi et al. (13), cis ligands ''mask'' human CD22 binding to synthetic multivalent sialoside probes unless the cells are first pretreated with sialidase or periodate. Indeed, masking by endogenous cis ligands has su...

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The B Cell Coreceptor CD22 Associates with AP50, a Clathrin-Coated Pit Adapter Protein, Via Tyrosine-Dependent Interaction

Cited by 47 publications

References 53 publications

CD22 EXON 12 deletion as a pathogenic mechanism of human B-precursor leukemia

CD22 EXON 12 deletion as a pathogenic mechanism of human B-precursor leukemia

Targeting of NPC1 to Late Endosomes Involves Multiple Signals, Including One Residing within the Putative Sterol-sensing Domain

Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact

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