Intracellular and extracellular leukemia inhibitory factor proteins have different cellular activities that are mediated by distinct protein motifs

Although many growth factors and cytokines have been shown to be localized within the cell and nucleus, the mechanism by which these molecules elicit a biological response is not well understood. The cytokine leukemia inhibit ory factor (LIF) provides a tractable experimental system to investigate th is problem, because translation of alternatively spliced transcripts result s in the production of differentially localized LIF proteins, one secreted from the cell and acting via cell surface receptors and the other localized within the cell. We have used overexpression analysis to demonstrate that extracellular and intracellular LIF proteins can have distinct cellular act ivities. Intracellular LIF protein is localized to both nucleus and cytopla sm and when overexpressed induces apoptosis that is inhibited by CrmA but n ot Bcl-2 expression. Mutational analysis revealed that the intracellular ac tivity was independent of receptor interaction and activation and reliant o n a conserved leucine-rich motif that was not required for activation of ce ll surface receptors by extracellular protein. This provides the first repo rt of alternate intracellular and extracellular cytokine activities that re sult from differential cellular localization of the protein and are mediate d by spatially distinct motifs.