Enhanced hematopoiesis by hematopoietic progenitor cells lacking intracellular adaptor protein, Lnk.
Hematopoietic stem cells (HSCs) give rise to variety of hematopoietic cells via pluripotential progenitors and lineage-committed progenitors and are responsible for blood production throughout adult life. Amplification of HSCs or progenitors represents a potentially powerful approach to the treatment of various blood disorders and to applying gene therapy by bone marrow transplantation. Lnk is an adaptor protein regulating the production of B cells. Here we show that Lnk is also expressed in hematopoietic progenitors in bone marrow, and that in the absence of Lnk, the number and the hematopoietic ability of progenitors are significantly increased. Augmented growth signals through c-Kit partly contributed to the enhanced hematopoiesis by lnk-/- cells. Lnk was phosphorylated by and associated with c-Kit, and selectively inhibited c-Kit-mediated proliferation by attenuating phosphorylation of Gab2 and activation of mitogen-activated protein kinase cascade. These observations indicate that Lnk plays critical roles in the expansion and function of early hematopoietic progenitors, and provide useful clues for the amplification of hematopoietic progenitor cells.
Takaki
Satoshi
S
Division of Immunology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. takakis@ims.u-tokyo.ac.jp
Morita
Hatsue
H
Tezuka
Yoshinari
Y
Takatsu
Kiyoshi
K
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D005786:Gene Expression Regulation / Q000502:physiology; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D015398:Signal Transduction; D018909:src Homology Domains / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; D011506:Proteins; D019009:Proto-Oncogene Proteins c-kit