c-CbI Interacts with CD38 and Promotes Retinoic Acid-Induced Differentiation and G0 Arrest of Human Myeloblastic Leukemia Cells

Retinoic acid (RA) is known to regulate cell growth and differentiation. In HL-60 human myeloblastic leukemia cells, it causes mitogen-activated protein kinase (MAPK) signaling leading to myeloid differentiation and Go cell cycle arrest. This communication reports that expression of the Cb1 adaptor caused enhanced extracellular signal-regulated kinase 2 activation and promoted RA-induced differentiation and Go-arrest. Stable transfectants ectopically expressing c-Ch1 underwent myeloid differentiation faster than wild-type (wt) cells when treated with RA. In contrast, c-Cb1 knockdown stable transfectants differentiated slower than wt cells when treated with RA. Cells ectopically expressing c-Cb1 had enhanced CD38 expression when treated with RA, and cells ectopically expressing CD38 had enhanced c-Cb1 expression, even without with RA, suggesting an interaction between c-Cb1 and CD38. Fluorescence resource energy transfer and coimmunoprecipitation showed that c-Cb1 and CD38 bind each other. RA causes the gradual down-regulation and eventual loss of c-Cb1 expression, resulting in loss of the Cb1-CD38 interaction, suggesting that c-Cb1 plays a relatively early role in promoting RA-induced differentiation. RA-induced differentiation can thus be propelled by c-Cb1 and by CD38, both of which bind together, enhance the expression of each other, and cause NIAPK signaling. There thus seems to be a cooperative role for c-Cb1 and CD38, reflected in their direct binding, in propulsion of RA-induced differentiation. [Cancer Res 2008;68(21):8761-9]