CD5 Binds to Interleukin-6 and Induces a Feed-Forward Loop with the Transcription Factor STAT3 in B Cells to Promote Cancer

Zhang, Chunyan; Hong, Xin; Zhang, Wang; Yazaki, Paul J.; Zhang, Zhifang; Le, Keith; Li, Wenzhao; Lee, Heehyoung; Kwak, Larry W.; Forman, Stephen J.; Jove, Richard; Yu, Hua

doi:10.1016/j.immuni.2016.04.003

Cited by 122 publications

(108 citation statements)

References 56 publications

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“…The importance of B cell subsets in cancer immunity was made apparent in a recent study demonstrating that IL-6 dependent activation of STAT3, which had long been associated with chronic inflammation in the tumor microenvironment [44,56,115], was confined to the subpopulation of CD5+, but not CD5− B cells [116]. CD5+ B cell numbers and STAT3 activation correlated with poor survival…”

Section: Perspectives and Final Thoughtsmentioning

confidence: 99%

B Lymphocytes and Cancer: A Love–Hate Relationship

2016

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Section: Perspectives and Final Thoughtsmentioning

confidence: 99%

B Lymphocytes and Cancer: A Love–Hate Relationship

2016

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“…Although CD5 is considered primarily to be a regulator of TCR and B cell receptor (BCR) signaling (and therefore complexed to TCR or BCR), a recent study demonstrated that IL-6 can signal via CD5 (Zhang et al, 2016). The identification of functional signaling through CD5 that appears independent of its antigen receptor regulatory functions suggests that it could be expressed and function independently of the antigen receptor complex.…”

mentioning

confidence: 99%

Human Group 1 Innate Lymphocytes Are Negative for Surface CD3ε but Express CD5

Roan¹,

Ziegler

2017

Immunity

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Simoni and colleagues recently published a mass cytometry (CyTOF)-based analysis of innate lymphoid cell (ILC) subsets across different human tissues (Simoni et al., 2017). Helper-type ILC1 cells were undetectable in these analyses, and the authors suggest that ILC1s reported in previous studies were likely attributable to T cell contamination. Although much of the heterogeneity and complexity within the ILC1 population remains to be fully delineated, we believe there is ample evidence that these cells constitute a unique population(s) clearly distinct from conventional T cells.

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“…Our data show that in CLL cells, CD5 contributes to STAT3 phosphorylation, as transfection of CLL cells with CD5-siRNA significantly downregulated CD5 mRNA and protein levels and markedly reduced the levels of serine pSTAT3. In addition, CD5-neutralizing antibodies, known to inhibit the activation of CD5, significantly reduced CD5 and serine pSTAT3 protein levels in CLL cells, likely because CD5 and STAT3 form a feed-forward loop (33). …”

Section: Discussionmentioning

confidence: 99%

Constitutive Phosphorylation of STAT3 by the CK2–BLNK–CD5 Complex

Rozovski

Harris

et al. 2017

Molecular Cancer Research

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In chronic lymphocytic leukemia (CLL), STAT3 is constitutively phosphorylated on serine 727 and plays a role in the pathobiology of CLL. However, what induces constitutive phosphorylation of STAT3 is currently unknown. Mass spectrometry was used to identify casein kinase 2 (CK2), a serine/threonine kinase that co-immunoprecipitated with serine phosphorylated STAT3 (pSTAT3). Furthermore, activated CK2 incubated with recombinant STAT3 induced phosphorylation of STAT3 on serine 727. Although STAT3 and CK2 are present in normal B- and T-cells, STAT3 is not constitutively phosphorylated in these cells. Further study found that CD5 and BLNK co-expressed in CLL, but not in normal B- or T-cells, are required for STAT3 phosphorylation. To elucidate the relationship of CD5 and BLNK to CK2 and STAT3, STAT3 was immunoprecipitated from CLL cells and CK2, CD5, and BLNK were detected in the immunoprecipitate. Conversely, STAT3, CD5, and BLNK were in the immunoprecipitate of CLL cells immunoprecipitated with CK2 antibodies. Furthermore, siRNA knockdown of CD5 or BLNK, or treatment with CD5-neutralizing antibodies significantly reduced the levels of serine pSTAT3 in CLL cells. Finally, confocal microscopy determined that CD5 is cell membrane bound and fractionation studies revealed that the CK2/CD5/BLNK/STAT3 complex remains in the cytoplasm, whereas serine pSTAT3 is shuttled to the nucleus. Implications These data show that the cellular proteins CK2, CD5, and BLNK are required for constitutive phosphorylation of STAT3 in CLL. Whether this protein complex phosphorylates other proteins or inhibiting its activity would have clinical benefit in patients has yet to be determined.

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CD5 Binds to Interleukin-6 and Induces a Feed-Forward Loop with the Transcription Factor STAT3 in B Cells to Promote Cancer

Cited by 122 publications

References 56 publications

B Lymphocytes and Cancer: A Love–Hate Relationship

B Lymphocytes and Cancer: A Love–Hate Relationship

Human Group 1 Innate Lymphocytes Are Negative for Surface CD3ε but Express CD5

Constitutive Phosphorylation of STAT3 by the CK2–BLNK–CD5 Complex

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