G6b-B: the “Y’s” and wherefores

G6b-B, which is encoded by a gene that is variously called G6b, C6orf25, or MPIG6B, is a platelet- and megakaryocyte-specific receptor that binds the tandem Src homology 2 domain-containing protein tyrosine phosphatases Shp2 and Shp1 upon phosphorylation of cytoplasmic immunoreceptor tyrosine-based inhibitory and switch motifs (ITIM and ITSM, respectively).^3,,,-7  Mice lacking G6b-B,⁸  or whose platelets lack Shp1 and Shp2,⁹  exhibit severe macrothrombocytopenia, defects in proplatelet formation, and aberrant platelet function.

Hofmann et al validate the relevance of findings made in G6b-B–deficient mice to human disease by demonstrating the association, in humans, of germ line loss-of-function mutations in G6b with congenital macrothrombocytopenia with focal myelofibrosis (cMFTM), which is a rare form of childhood myelofibrosis. Furthermore, they demonstrate that G6b-B–deficient mice also exhibit hematologic and histopathologic features of myelofibrosis, which can be rescued by expression of human G6b-B. Together with the recent report of thrombocytopenia in a family with a truncation mutation in G6b,¹⁰  these results strongly support the conclusion that G6b-B is required in both mice and humans for normal production of platelets by megakaryocytes in the bone marrow.

Geer et al use mice engineered to express a mutant form of G6b-B in which the ITIM and ITSM tyrosine residues were substituted with phenylalanine (G6b-B diY/F) to address the mechanism by which G6b-B functions in megakaryocytes and platelets. Specifically, they demonstrate that G6b-B diY/F mice phenocopy the severe macrothrombocytopenia, defective proplatelet production, aberrant platelet function, and myelofibrosis that are characteristic of G6b-B–deficient mice and humans. These results indicate that G6b-B requires its ITIM and ITSM, presumably to become phosphorylated and bind Shp1 and Shp2, to support normal platelet production by megakaryocytes (see figure).

The association of G6b-B with inherited myelofibrosis has implications for future studies. First, these studies justify additional clinical research to determine the extent to which loss-of-function mutations in G6b contribute to primary myelofibrosis in children, the causes of which are notably distinct from the identically named adult disease and remain largely uncharacterized.¹¹  Second, more basic scientific work is needed to identify the ligands with which G6b-B normally interacts in the bone marrow, the kinases that are responsible for its phosphorylation, and how it works with Shp1/2 to support normal hematopoiesis and (pro)platelet production.¹²