The Journal of Immunology, Vol 156, Issue 8 2933-2940, Copyright © 1996 by American Association of Immunologists

ARTICLES

Modulation of megakaryocytopoiesis by human macrophage-stimulating protein, the ligand for the RON receptor

N Banu, DJ Price, R London, B Deng, M Mark, PJ Godowski and H Avraham
Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.

We observed that human megakaryocytes expressed the heterodimeric tyrosine kinase RON, which serves as a receptor for macrophage- stimulating protein (MSP). MSP appears to be structurally related to hepatocyte growth factor (HGF), which is a pleiotropic growth factor for a broad spectrum of tissues and cell types. The effects of human rMSP and rHGF on permanent human megakaryocytic cell lines as well as on human and murine primary marrow megakaryocytes were studied. MSP enhanced the maturation of the primary bone marrow megakaryocytes and human megakaryocytic cell lines, CMK and DAMI, as assessed by an increase in ploidy content. The increase in ploidy was blocked by specific Abs for MSP and by anti-IL-6 Abs. MSP treatment of primary human marrow megakaryocytes, DAMI cells, or CMK cells resulted in enhanced secretion of IL-6. The addition of MSP to cultures of immature murine megakaryoblasts showed a significant growth response, similar to that of exogenous IL-6. This increased growth of immature murine megakaryoblasts in response to MSP was abrogated either by Abs against MSP or by neutralizing mAbs to IL-6. HGF, over a range of concentrations (10 to 100 ng/ml) alone or in combination with IL-3, granulocyte-macrophage-CSF, or IL-6, had no effect on differentiation of human or murine marrow megakaryocytes. These results indicate that megakaryocytes express a novel tyrosine kinase receptor (RON), and that its ligand, MSP, appears capable of regulating megakaryocyte maturation, possibly via an autocrine mechanism mediated by induction of the cytokine IL-6.

This article has been cited by other articles:

				D. Angeloni, A. Danilkovitch-Miagkova, A. Miagkov, E. J. Leonard, and M. I. Lerman The Soluble Sema Domain of the RON Receptor Inhibits Macrophage-stimulating Protein-induced Receptor Activation J. Biol. Chem., January 30, 2004; 279(5): 3726 - 3732. [Abstract] [Full Text] [PDF]

				K. A. Hess, S. E. Waltz, E. L. Chan, and S. J.F. Degen Receptor Tyrosine Kinase Ron Is Expressed in Mouse Reproductive Tissues During Embryo Implantation and Is Important in Trophoblast Cell Function Biol Reprod, April 1, 2003; 68(4): 1267 - 1275. [Abstract] [Full Text] [PDF]

				A. Forgie, S. Wyatt, P. H. Correll, and A. M. Davies Macrophage stimulating protein is a target-derived neurotrophic factor for developing sensory and sympathetic neurons Development, March 1, 2003; 130(5): 995 - 1002. [Abstract] [Full Text] [PDF]

				A. Danilkovitch-Miagkova, A. Miagkov, A. Skeel, N. Nakaigawa, B. Zbar, and E. J. Leonard Oncogenic Mutants of RON and MET Receptor Tyrosine Kinases Cause Activation of the {beta}-Catenin Pathway Mol. Cell. Biol., September 1, 2001; 21(17): 5857 - 5868. [Abstract] [Full Text] [PDF]

				R. C. Wahl, R.-Y. Hsu, J. L. Huff, M. A. Jelinek, K. Chen, P. Courchesne, S. D. Patterson, J. T. Parsons, and A. A. Welcher Chicken Macrophage Stimulating Protein Is a Ligand of the Receptor Protein-tyrosine Kinase Sea J. Biol. Chem., September 10, 1999; 274(37): 26361 - 26368. [Abstract] [Full Text] [PDF]

				R. S. Muraoka, S. E. Waltz, and S. J. F. Degen Expression of Hepatocyte Growth Factor-Like Protein Is Repressed by Retinoic Acid and Enhanced by Cyclic Adenosine 3',5'-Monophosphate Response Element-Binding Protein (CREB)-Binding Protein (CBP) Endocrinology, January 1, 1999; 140(1): 187 - 196. [Abstract] [Full Text]

				J.-F. Wang, Z.-Y. Liu, and J. E. Groopman The alpha -Chemokine Receptor CXCR4 Is Expressed on the Megakaryocytic Lineage From Progenitor to Platelets and Modulates Migration and Adhesion Blood, August 1, 1998; 92(3): 756 - 764. [Abstract] [Full Text] [PDF]

				M.-H. Wang, F. M. Julian, R. Breathnach, P. J. Godowski, T. Takehara, W. Yoshikawa, M. Hagiya, and E. J. Leonard Macrophage Stimulating Protein (MSP) Binds to Its Receptor via the MSP beta  Chain J. Biol. Chem., July 4, 1997; 272(27): 16999 - 17004. [Abstract] [Full Text] [PDF]