Calcium- and integrin-binding protein 1 regulates megakaryocyte ploidy, adhesion, and migration

• Published in: Blood 2012-01, Vol.119 (3), p.838-846
• Main Authors: Kostyak, John C., Naik, Meghna U., Naik, Ulhas P.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Platelets - cytology; Blood Platelets - metabolism; Blotting, Western; Calcium - pharmacology; Calcium-Binding Proteins - physiology; Cell Adhesion - physiology; Cell Movement - physiology; Chemokine CXCL12 - metabolism; Hematologic and hematopoietic diseases; Hematopoiesis and Stem Cells; Medical sciences; Megakaryocytes - cytology; Megakaryocytes - physiology; Mice; Mice, Knockout; Phosphorylation; Platelets and Thrombopoiesis; Ploidies; Protein Binding; Signal Transduction; Thrombopoiesis; Thrombopoietin - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-04-346098

Megakaryocytes are large, polyploid cells that produce platelets. We have previously reported that calcium- and integrin-binding protein 1 (CIB1) regulates endomitosis in Dami cells. To further characterize the role of CIB1 in megakaryopoiesis, we used a Cib1−/− mouse model. Cib1−/− mice have more platelets and BM megakaryocytes than wild-type (WT) controls (P < .05). Furthermore, subsequent analysis of megakaryocyte-CFU production revealed an increase with Cib1 deletion compared with WT (P < .05). In addition, BM from Cib1−/− mice, cultured with thrombopoietin (TPO) for 24 hours, produced more highly polyploid megakaryocytes than WT BM (P < .05). Subsequent analysis of TPO signaling revealed enhanced Akt and ERK1/2 phosphorylation, whereas FAKY925 phosphorylation was reduced in Cib1−/− megakaryocytes treated with TPO. Conversely, platelet recovery in Cib1−/− mice after platelet depletion was attenuated compared with WT (P < .05). This could be the result of impaired adhesion and migration, as adhesion to fibrinogen and fibronectin and migration toward an SDF-1α gradient were reduced in Cib1−/− megakaryocytes compared with WT (P < .05). In addition, Cib1−/− megakaryocytes formed fewer proplatelets compared with WT (P < .05), when plated on fibrinogen. These data suggest that CIB1 plays a dual role in megakaryopoiesis, initially by negatively regulating TPO signaling and later by augmenting proplatelet production.