ITIM receptors: more than just inhibitors of platelet activation

Carmen H Coxon, Mitchell J Geer, Yotis A Senis

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)
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Since their discovery, immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptors have been shown to inhibit signaling from immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors in almost all hematopoietic cells, including platelets. However, a growing body of evidence has emerged demonstrating that this is an over-simplification, and that ITIM-containing receptors are versatile regulators of platelet signal transduction, with functions beyond inhibiting ITAM-mediated platelet activation. PECAM-1 was the first ITIM-containing receptor identified in platelets and appeared to conform to the established model of ITIM-mediated attenuation of ITAM-driven activation. PECAM-1 was therefore widely accepted as a major negative regulator of platelet activation and thrombosis for many years, but more recent findings suggest a more complex role for this receptor, including the facilitation of αIIbβ3-mediated platelet functions. Since the identification of PECAM-1, several other ITIM-containing platelet receptors have been discovered. These include G6b-B, a critical regulator of platelet reactivity and production, and the non-canonical ITIM-containing receptor TLT-1, which is localized to α-granules in resting platelets, binds fibrinogen, and acts as a positive regulator of platelet activation. Despite structural similarities and shared binding partners, including the Src homology 2 domain-containing protein-tyrosine phosphatases Shp1 and Shp2, knockout and transgenic mouse models have revealed distinct phenotypes and non-redundant functions for each ITIM-containing receptor in the context of platelet homeostasis. These roles are likely influenced by receptor density, compartmentalization, and as yet unknown binding partners. In this review, we discuss the diverse repertoire of ITIM-containing receptors in platelets, highlighting intriguing new functions, controversies and future areas of investigation.

Original languageEnglish
Pages (from-to)3407-3418
Number of pages12
Issue number26
Early online date2 May 2017
Publication statusPublished - 29 Jun 2017


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