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J. Biol. Chem., Vol. 283, Issue 11, 6997-7006, March 14, 2008

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Osteopontin Regulates Actin Cytoskeleton and Contributes to Cell Proliferation in Primary Erythroblasts^*

Jeong-Ah Kang¹, Ying Zhou¹, Tahlia L. Weis², Hui Liu, Jodie Ulaszek, Nilesh Satgurunathan, Li Zhou^¶, Koen van Besien, John Crispino, Amit Verma^¶, Philip S. Low, and Amittha Wickrema³

From the Department of Medicine, University of Chicago, Chicago, Illinois 60637, the Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, and the ^¶Department of Medicine, Albert Einstein University, New York, New York 10461

Erythropoietin and stem cell factor are the key cytokines that regulate early stages of erythroid differentiation. However, it remains undetermined whether additional cytokines also play a role in the differentiation program. Here, we report that osteopontin (OPN) is highly expressed and secreted by erythroblasts during differentiation. We also demonstrate that OPN-deficient human and mouse erythroblasts exhibit defects in F-actin filaments, and addition of exogenous OPN to OPN-deficient erythroblasts restored the F-actin filaments in these cells. Furthermore, our studies demonstrate that OPN contributes to erythroblast proliferation. OPN knock-out male mice exhibit lower hematocrit and hemoglobin levels compared with their wild-type counterparts. We also show that OPN mediates phosphorylation or activation of multiple proteins including Rac-1 GTPase and the actin-binding protein, adducin, in human erythroblasts. In addition, we show that the OPN effects include regulation of intracellular calcium in human erythroblasts. Finally, we demonstrate that human erythroblasts express CD44 and integrins β₁ and ₄, three known receptors for OPN, and that the integrin β₁ receptor is involved in transmitting the proliferative signal. Together these results provide evidence for signal transduction by OPN and contribution to multiple functions during the erythroid differentiation program in human and mouse.

Received for publication, August 13, 2007 , and in revised form, December 6, 2007.

^* This work was supported in part by National Institutes of Health Grants CA98550 (to A. W.) and HL082946 (to A. V.) and a University of Chicago Cancer Research Center seed grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Supported by National Institutes of Health Training Grant T32-GM008296-17.

³ To whom correspondence should be addressed: Hematology/Oncology Section, MC2115, University of Chicago, 5841 South Maryland Ave., Chicago, IL 60637. E-mail: Awickrem{at}medicine.bsd.uchicago.edu.

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