TYORISINE PHOSPHATASE SHP2 IN HEMATOPOIETIC STEM CELL PROPERTY MAINTENANCE

Rhode Island Hospital, Providence RI

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The long term goal of this study is to elucidate the function of protein tyrosine phosphatases in normal hematopoiesis and hematopoietic disorders. We will focus on the role of the Src homology 2 (SH2) domain containing protein tyrosine phosphatase Shp2 (PTPN11) based on our recent data collected from hematopoietic cell/stage-specific Shp2 deficient mice. We previously generated a Ptpn11 floxed allele, inducible deletion of Shp2 in hematopoietic cells via "Cre-loxP" system causes marrow aplasia, substantial reduction of hematopoietic stem cells (HSC) and decreased colony formation of myeloid and erythroid lineages. Shp2 mutant mice appear smaller, not healthy and were severely anemic. In contrast, mice lacking Shp2 expression since granulocyte (G)-macrophage (M) progenitor (GMP) stage, appear normal, but developed osteopetreosis as they aged. Marrow cells from these mutant mice show reduction in the number and size of CFU-M and CFU-GM colonies. Bone marrow derived macrophages (BMM) lacking Shp2 expression display retarded growth and defective Ras/Erk activation in response to both macrophage-colony stimulating factor (M-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF), PI3 kinase/Akt signaling was mis-regulated as well. Our preliminary data strongly implicate a critical role for Shp2 in HSC maintenance and hematopoiesis, and Shp2 may have differential function in various types of hematopoietic cells and/or at different hematopoietic stage. Our central hypotheses are: 1) Shp2 is essential for the self-renewal and/or multiple lineage differentiation of HSC;2) Shp2 is required for myelopoiesis, myelomonocytic cell proliferation and differentiation. We intend to fill the following knowledge gaps: 1) Is the defective hematopoiesis due to Shp2 deficiency HSC autonomous? 2) If so, what's the role of Shp2 in HSC? Does Shp2 play a role for HSC self-renewal, survival, and/or multiple lineage differentiation? 3) What is the primary signaling pathway(s) by which Shp2 regulates HSC properties? 4) Does the defective Ras/Erk and PI3 kinase/Akt signaling in Shp2 deficient myeloid cells account for their retarded growth, and affect their differentiation? Elucidating the molecular and cellular mechanism through which Shp2 modulates HSC self-renewal and multi-lineage differentiation will provide insights into mobilizing HSC for regenerative medicine and understanding how Shp2 mutations cause human hematopoietic diseases, such as juvenile myelomonocytic leukemia1 (JMML) and myeloid proliferative disorders (MPD).