Characterization of the megakaryocyte demarcation membrane system and its role in thrombopoiesis

Harald Schulze, Manav Korpal, Jonathan Hurov, Sang We Kim, Jinghang Zhang, Lewis C. Cantley, Thomas Graf, Ramesh A. Shivdasani

Research output: Contribution to journalArticle

136 Scopus citations

Abstract

To produce blood platelets, megakaryocytes elaborate proplatelets, accompanied by expansion of membrane surface area and dramatic cytoskeletal rearrangements. The invaginated demarcation membrane system (DMS), a hallmark of mature cells, has been proposed as the source of proplatelet membranes. By direct visualization of labeled DMS, we demonstrate that this is indeed the case. Late in megakaryocyte ontogeny, the DMS gets loaded with PI-4,5-P 2, a phospholipid that is confined to plasma membranes in other cells. Appearance of PI-4,5-P2 in the DMS occurs in proximity to PI-5-P-4-kinase α (PIP4Kα), and short hairpin (sh) RNAmediated loss of PIP4Kα impairs both DMS development and expansion of megakaryocyte size. Thus, PI-4,5-P2 is a marker and possibly essential component of internal membranes. PI-4,5-P2 is known to promote actin polymerization by activating Rho-like GTPases and Wiskott-Aldrich syndrome (WASp) family proteins. Indeed, PI-4,5-P2 in the megakaryocyte DMS associates with filamentous actin. Expression of a dominant-negative N-WASp fragment or pharmacologic inhibition of actin polymerization causes similar arrests in proplatelet formation, acting at a step beyond expansion of the DMS and cell mass. These observations collectively suggest a signaling pathway wherein PI-4,5-P2 might facilitate DMS development and local assembly of actin fibers in preparation for platelet biogenesis.

Original languageEnglish (US)
Pages (from-to)3868-3875
Number of pages8
JournalBlood
Volume107
Issue number10
DOIs
StatePublished - May 15 2006

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Schulze, H., Korpal, M., Hurov, J., Kim, S. W., Zhang, J., Cantley, L. C., Graf, T., & Shivdasani, R. A. (2006). Characterization of the megakaryocyte demarcation membrane system and its role in thrombopoiesis. Blood, 107(10), 3868-3875. https://doi.org/10.1182/blood-2005-07-2755