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Influence of PI‐3K/Akt pathway on Wnt signalling in regulating myeloid progenitor cell proliferation. Evidence for a role of autocrine/paracrine Wnt regulation
Author(s) -
Nteliopoulos Georgios,
Marley Stephen B.,
Gordon Myrtle Y.
Publication year - 2009
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2009.07823.x
Subject(s) - autocrine signalling , wnt signaling pathway , microbiology and biotechnology , paracrine signalling , pi3k/akt/mtor pathway , protein kinase b , lrp6 , progenitor cell , cell growth , biology , chemistry , signal transduction , cancer research , stem cell , receptor , biochemistry
Summary The regulation of myeloid progenitor cell (granulocyte‐macrophage colony‐forming units, CFU‐GM) proliferation/differentiation by the Wnt and phosphatidylinositol‐3 kinase (PI‐3K) pathways was investigated using a colony‐replating assay. The PI‐3K pathway promoted differentiation of interleukin‐3 (IL‐3)‐stimulated myelopoiesis via Akt, because inhibition of the PI‐3K/Akt pathway with LY294002 or SH‐5 increased proliferation. The involvement of canonical and non‐canonical Wnt pathways was investigated using Wnt3a and Wnt5a respectively. Addition of the recombinant Wnts to IL‐3 increased CFU‐GM proliferation. Dkk‐1, when combined with the Wnt proteins, abrogated the effects of Wnt3a but not Wnt5a. Surprisingly, the addition of Dkk‐1 to LY294002 or SH‐5 blocked their proliferative effects. We hypothesized that increased proliferation induced by PI‐3K/Akt inhibitors was not mediated by downstream activation of the Wnt pathway but by induced endogenous production/release of Wnt proteins. The addition of SH‐5 to IL‐3 created an autocrine Wnt loop in CD34 + cells, resulting in the phosphorylation of lipoprotein‐receptor‐related‐protein 6. Furthermore, the addition of medium conditioned by CD34 + cells cultured in IL‐3 + SH‐5 to IL‐3 increased CFU‐GM proliferation. This effect was abrogated by Dkk‐1, suggesting that a Wnt in the conditioned medium increased proliferation. In summary, IL‐3 via the PI‐3K pathway promoted differentiation of myeloid progenitor cells through a decrease of endogenous Wnt production/release.