Point mutations within a dimer interface homology domain of c-Mpl induce constitutive receptor activity and tumorigenicity.

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Abstract
C‐Mpl, a receptor for thrombopoietin (TPO), belongs to the haemopoietin/cytokine receptor superfamily, a group of cell surface molecules characterized by conserved sequence motifs within their ligand binding domains. A recurring mechanism for the activation of haemopoietin receptors is the formation of functional complexes by receptor subunit oligomerization. Within the growth hormone receptor, a cluster of extracellular amino acids forms a dimer interface domain that stabilizes ligand‐induced homodimers. This domain appears to be functionally conserved in the erythropoietin (EPO) receptor because substitution of cysteines for residues in the analogous region causes EPO‐independent receptor activation via disulfide‐linked homodimerization. This report identifies an homologous domain within the c‐Mpl receptor. The substitution of cysteine residues for specific amino acids in the dimer interface homology regions of c‐Mpl induced constitutive receptor activity. Factor‐dependent FDC‐P1 and Ba/F3 cells expressing the active receptor mutants no longer required exogenous factors and proliferated autonomously. The results imply that the normal process of TPO‐stimulated Mpl activation occurs through receptor homodimerization and is mediated by a conserved haemopoietin receptor dimer interface domain. Moreover, cells expressing activated mutant Mpl receptors were tumorigenic in transplanted mice. Thus, like v‐mpl, its viral counterpart, mutated forms of the cellular mpl gene also have oncogenic potential.