Publication details
Activation of AKT following Beta 1 integrin ligation modulates survival of B cell acute lymphoblastic leukemia cells
| Authors | |
|---|---|
| Year of publication | 2000 |
| Type | Article in Periodical |
| Magazine / Source | Blood |
| MU Faculty or unit | |
| Citation | |
| Field | Oncology and hematology |
| Keywords | leukemia; survival; integrins; AKT |
| Description | Progenitor B cell acute lymphoblastic leukemia (ALL) cells employ several adhesion receptors to interact with stromal cells and extracellular matrix proteins in the BM microenvironment. These adhesive interactions have been implicated in leukemic cell survival. Ligation of Beta1 integrins on the surface of the pre- and pro-B ALL cells induces multiple signal transduction pathways. We have used the pro-B ALL cell line REH which does not express B cell receptors and possesses a Tel-Aml translocation to investigate the role of Beta1 integrins in leukemic cell survival. Following Beta1 integrin crosslinking, the antiapoptotic serine/threonine kinase Akt was activated in REH cells. Since PI3 kinase activates Akt, we evaulated the effects of the PI3 kinase inhibitor LY 294002 on cell survival and apoptosis. LY 294002 accelerated apoptotic cell death when REH cells were incubated in serum free medium. In contrast, the MAP kinase inhibitor PD 98089 had no effect indicating that the MAP kinase pathway was not involved in REH survival. However, the tyrosine (tyr) kinase inhibitor herbimycin-A also caused apoptosis of REH cells indicating a possible role of tyr kinase(s) in the activation of Akt and thus cell survival. To elucidate the mechanism of Akt actiovation in REH cells after Beta1 integrin ligation, we investigated the possible role of three tyr kinases which are activated upon integrin ligation: FAK, RAFTK (pyk2 or CAKbeta) and syk. We found that the expression and tyr phosphorylation of RAFTK following beta1 interin ligation was higher compared to FAK, and syk was not tyr phosphorylated. Since RAFTK is highly expressed and tyr phosphorylated in REH cells, we hypothesized that RAFTK may play a role in the cell survival and in the activation of Akt. Pretreatment of REH cells with PI3 kinase inhibitor LY 294002 before crosslinking of Beta1 integrins did not inhibit tyr phosphorylation of RAFTK or the adaptor protein HEF1 indicating that RAFTK and Akt act in the same pathway. To futher demonstrate that RAFTK was linked to Akt activation we performed transient transfection of Akt in mouse fibroblast cell line lacking FAK but expressing RAFTK. Following plating on fibronectin we observed increased RAFTK tyr phosphorylation as well as Akt activation. These studies support the hypothesis that Beta1 integrin activaton of RAFTK likely plays an important role in Akt activation and therefore the regulation of B cell ALL survival. These pathways may be potential targets for therapy of ALL. |