The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin signaling network and the control of normal myelopoiesis.
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a central role in cell growth, proliferation, differentiation, and survival under physiological conditions. Aberrant regulation of the PI3K/Akt/mTOR signal transduction network has been observed in a wide range of neoplasias, including malignant hematological disorders. This observation suggests that this signaling cascade could also play a critical role during normal hematopoiesis, a highly regulated process which results in the formation of all blood lineages. The development of blood cells comprises a complex series of events which are mainly regulated through the actions of cytokines, a large family of extracellular ligands than can stimulate many biological responses in a wide array of cell types. Several of these cytokines are known to activate the PI3K/Akt/mTOR signal transduction network and thus regulate proliferation, survival, and differentiation events during hematopoiesis. Moreover, hematopoiesis is strictly dependent on the correct functions of the bone marrow microenvironment. Here, we review the evidence which links the signals emanating from the PI3K/Akt/mTOR cascade with the functions of hematopoietic stem cells and the process of lineage commitment, which then gives rise to myeloid lineage-restricted cells. We then further highlight the key role played by the PI3K/Akt/mTOR network during erythropoiesis, megakaryocytopoiesis, and granulo-cytopoiesis/monocytopoiesis.
Department of Human Anatomy, University of Bologna, Bologna, Italy. alberto.martelli@gmail.com
Alberto M
AM
Martelli
Francesca
F
Chiarini
Camilla
C
Evangelisti
Cecilia
C
Grimaldi
Andrea
A
Ognibene
Lucia
L
Manzoli
Anna Maria
AM
Billi
James A
JA
McCubrey
D000818:Animals; D004920:Erythropoiesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D038042:Myelopoiesis / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D034061:Thrombopoiesis / Q000502:physiology
D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human