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Blood, 15 November 2004, Vol. 104, No. 10, pp. 3004-3005.
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HEMATOPOIESIS
Comment on Kanaji et al, page 3161
A tail with a leading role in megakaryocytes: the glycoprotein Ib
Katya Ravid
BOSTON UNIVERSITY SCHOOL OF MEDICINE
Megakaryocytes possess a unique internal programming that allows an evolving response to a cytokine, thrombopoietin (TPO), including cellular expansion followed by polyploidization and maturation. The study of this lineage has been greatly aided by analysis of genetically modified mice and/or models of related human syndromes.
The Bernard-Soulier syndrome is associated with abnormal bone marrow megakaryocytes with poorly developed demarcation membranes, giant circulating platelets, and a reduced platelet count (coined as macrothrombocytopenia). The genetic basis of this syndrome has long been recognized as caused by mutations that impair expression of a multisubunit receptor, the glycoprotein (GP) Ib-IX complex. The mouse phenotype mimicking the human Bernard-Soulier syndrome can be salvaged by expression of a human GP Ib transgene.1
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GP Ib expression, megakaryocyte proliferation, and differentiation. See the complete figure in the article beginning on page 3161.
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In this issue of Blood, Kanaji and colleagues describe a series of elegant experiments that explore the importance of the cytoplasmic tail of GP Ib in rescuing mice from the Bernard-Soulier–like phenotypes. Using the megakaryocyte-specific platelet factor 4 promoter,2 these investigators generated a transgenic mouse line expressing onto a GP Ib knock-out background1 a variant human GP Ib subunit lacking the 6 terminal residues (605-610) on the cytoplasmic tail. This system was compared with the rescue of the GP Ib null phenotype produced by a wild-type human GP Ib allele. The cytoplasmic tail was chosen as a target mainly because it has been previously shown to be critical for binding to the signal transduction protein 14-3-3 .3 The latter has been implicated in various processes that have been described by others to affect megakaryocyte proliferation and/or ploidy (eg, Drachman et al4). 14-3-3 influences intracellular signaling pathways (eg, Raf, MLK, MEKK, phosphatidylinositol-3 [PI-3] kinase, IRS-1), cell cycling (eg, Cdc25, Wee1, CDK2, centrosome), apoptosis (eg, BAD, ASK-1), and the regulation of transcription (eg, FKHRL1, DAF-16, p53, TAZ, TLX-2, histone deacetylase).5
The phenotypes in the new transgenic models generated by Kanaji et al illustrate an involvement of the GP Ib cytoplasmic tail in thrombopoietin-mediated events, including megakaryocyte proliferation, polyploidization, and the expression of apoptotic markers in maturing megakaryocytes. Furthermore, this study demonstrates an increase in thrombopoietin-mediated Akt phosphorylation in the truncated variant, leading the authors to hypothesize that a GP Ib/14-3-3/PI-3 kinase complex is involved in regulating thrombopoietin-mediated responses (see figure).
A hypothesis is presented whereby the cytoplasmic tail of GP Ib sequesters signaling proteins, such as 14-3-3 and PI3K, and down-regulates the Akt-dependent pathway. The authors speculate that in the truncated GP Ib variant, a shift in the PI3K/Akt axis results in increased Akt activation and downstream consequences of increased endomitosis and accumulation of a greater percentage of high ploidy megakaryocytes. Although this is an appealing contention, it awaits further analyses to demonstrate a GP Ib/14-3-3/PI-3 kinase complex in vivo. It will also be of great interest to examine whether excess (via overexpression) of full-length versus a cytoplasmic tail portion of GP Ib results in greater sequestration of this complex and hindrance of thrombopoietin-related signaling.
Finally, while this study demonstrates that the molecular basis of the macrothrombocytopenia is linked to an absence of the cytoplasmic tail of the GP Ib subunit of the GP Ib-IX complex, the authors rightfully point out that a role for the extracytoplasmic domains of the complex cannot be excluded.
References
- Ware J, Russell S, Ruggeri ZM. Generation and rescue of a murine model of platelet dysfunction: the Bernard-Soulier syndrome. Proc Natl Acad Sci U S A. 2000;97: 2803-2808.[Abstract/Free Full Text]
- Ravid K, Beeler DL, Rabin MS, Ruley HE, Rosenberg RD. Selective targeting of gene products with the megakaryocyte platelet factor 4 promoter. Proc Natl Acad Sci U S A. 1991;88: 1521-1525.[Abstract/Free Full Text]
- Feng S, Christodoulides N, Reséndiz JC, Berndt MC, Kroll MH. Cytoplasmic domains of GpIb and GpIb regulate 14-3-3 binding to GpIb/IX/V. Blood. 2000;95: 551-557.[Abstract/Free Full Text]
- Drachman JG, Rojnuckarin P, Kaushansky K. Thrombopoietin signal transduction: studies from cell lines and primary cells. Methods. 1999;17: 238-249.[CrossRef][Medline]
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- Fu H, Subramanian RR, Masters SC. 14-3-3 proteins: structure, function and regulation. Annu Rev Pharmacol Toxicol. 2000;40: 617-647.[CrossRef][Medline]
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Related Article in Blood Online:
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Megakaryocyte proliferation and ploidy regulated by the cytoplasmic tail of glycoprotein Ib
- Taisuke Kanaji, Susan Russell, Janet Cunningham, Kenji Izuhara, Joan E. B. Fox, and Jerry Ware
Blood 2004 104: 3161-3168.
[Abstract]
[Full Text]
[PDF]
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