Tensin2 is a novel mediator in thrombopoietin (TPO)-induced cellular proliferation by promoting Akt signaling
Volume 10, Issue 11
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June 1, 2011
Pages 1838 - 1844http://dx.doi.org/10.4161/cc.10.11.15776
Authors: Andre Scott Jung, Alexis Kaushansky, Gavin MacBeath and Kenneth Kaushansky View affiliations
Thrombopoietin (TPO) and its receptor c-Mpl are essential in the regulation of the hematopoietic stem and progenitors cells as well as for the differentiation of megakaryocytes into mature platelets. Once TPO binds to its receptor, an intracellular signaling process is initiated through Janus kinase (JAK-2)-induced phosphorylation of the c-Mpl intracellular domain. Although some protein mediators that transmit the effects of TPO have been identified, many remain undiscovered. Using an unbiased approach with peptide microarrays that contained virtually every Src Homology (SH)2 and Phosphotyrosine Binding (PTB) domains in the human genome, we discovered a previously unreported interaction between c-Mpl at phospho-Tyrosine631 (pY631) and Tensin2, a protein for which limited information is available. Confirming the findings of the microarrays, we discovered that Tensin2 co-precipitates with a pY631 bearing peptide. Furthermore, we found that Tensin2 becomes phosphorylated in a TPO dependent manner. The functional consequence of Tensin2 was tested via knockdown of Tensin2, which dramatically decreased TPO-dependent cellular proliferation of UT7-TPO cell line as well as their activation of Akt signaling. These studies affirm the use of these arrays as an unbiased screening tool of protein-protein interactions. We conclude that Tensin2 is an important new mediator in TPO/c-Mpl pathway and has a positive affect on cellular growth, at least in part through its effect on the PI3K/Akt signaling.