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Siglecs that Associate with DAP12

  • Takashi AngataEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1204)

Abstract

Siglecs are a family of transmembrane receptor-like glycan-recognition proteins expressed primarily on leukocytes. Majority of Siglecs have an intracellular sequence motif called immunoreceptor tyrosine-based inhibitory motif (ITIM) and associate with Src homology region 2 domain-containing tyrosine phosphatase-1 (SHP-1), and negatively regulate tyrosine phosphorylation-mediated intracellular signaling events. On the other hand, some Siglecs have a positively charged amino acid residue in the transmembrane domain and associate with DNAX activation protein of 12 kDa (DAP12), which in turn recruits spleen tyrosine kinase (Syk). These DAP12-associated Siglecs play diverse functions. For example, Siglec-15 is conserved throughout vertebrate evolution and plays a role in bone homeostasis by regulating osteoclast development and function. Human Siglec-14 and -16 have inhibitory counterparts (Siglec-5 and -11, respectively), which show extremely high sequence similarity with them at the extracellular domain but interact with SHP-1. The DAP12-associated Siglec in such “paired receptor” configuration counteracts the pathogens that exploit the inhibitory counterpart. Polymorphisms (mutations) that render DAP12-associated inactive Siglecs are found in humans, and some of these appear to be associated with sensitivity or resistance of human hosts to bacterially induced conditions. Studies of mouse Siglec-H have revealed complex and intriguing functions it plays in regulating adaptive immunity. Many questions remain unanswered, and further molecular and genetic studies of DAP12-associated Siglecs will yield valuable insights with translational relevance.

Keywords

Siglec DAP12 ITAM Syk Paired receptors 

Notes

Acknowledgements

The work in the author’s laboratory has been supported by intramural funding from Academia Sinica and extramural funding from the Ministry of Science and Technology, Taiwan [MOST 104-2311-B-001-017-MY3, 105-2627-M-007-001, and 106-2321-B-001-032].

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© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  1. 1.Institute of Biological Chemistry, Academia SinicaTaipeiTaiwan

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