Dynamins 2 and 3 control the migration of human megakaryocytes by regulating CXCR4 surface expression and ITGB1 activity

Praveen K. Suraneni, Seth J. Corey, Michael J. Hession, Rameez Ishaq, Arinola Awomolo, Shirin Hasan, Chirag Shah, Hui Liu, Amittha Wickrema, Najet Debili, John D Crispino, Elizabeth A Eklund, Yolande Chen

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Megakaryocyte (MK) migration from the bone marrow periosteal niche toward the vascular niche is a prerequisite for proplatelet extension and release into the circulation. The mechanism for this highly coordinated process is poorly understood. Here we show that dynasore (DNSR), a small-molecule inhibitor of dynamins (DNMs), or short hairpin RNA knockdown of DNM2 and DNM3 impairs directional migration in a human MK cell line or MKs derived from cultured CD341 cells. Because cell migration requires actin cytoskeletal rearrangements, we measured actin polymerization and the activity of cytoskeleton regulator RhoA and found them to be decreased after inhibition of DNM2 and DNM3. Because SDF-1a is important for hematopoiesis, we studied the expression of its receptor CXCR4 in DNSR-treated cells. CXCR4 expression on the cell surface was increased, at least partially because of slower endocytosis and internalization after SDF-1a treatment. Combined inhibition of DNM2 and DNM3 or forced expression of dominant-negative Dnm2-K44A or GTPase-defective DNM3 diminished b1 integrin (ITGB1) activity. DNSRtreated MKs showed an abnormally clustered staining pattern of Rab11, a marker of recycling endosomes. This suggests decreased recruitment of the recycling pathway in DNSR-treated cells. Altogether, we show that the GTPase activity of DNMs, which governs endocytosis and regulates cell receptor trafficking, exerts control on MK migration toward SDF-1a gradients, such as those originating from the vascular niche. DNMs play a critical role in MKs by triggering membrane-cytoskeleton rearrangements downstream of CXCR4 and integrins.

Original languageEnglish (US)
Pages (from-to)3540-3552
Number of pages13
JournalBlood Advances
Volume2
Issue number23
DOIs
StatePublished - Dec 11 2018

ASJC Scopus subject areas

  • Hematology

Fingerprint Dive into the research topics of 'Dynamins 2 and 3 control the migration of human megakaryocytes by regulating CXCR4 surface expression and ITGB1 activity'. Together they form a unique fingerprint.

Cite this