Abstract

Transforming growth factor- (TGF-) signals through a heteromeric complex of related type I and type II serine/threonine kinase receptors. In Mv1Lu cells the type I receptor TRI mediates TGF--induced gene expression and growth inhibition, while the closely related type I receptors Tsk7L and TSR1 are inactive in these responses. Using chimeras between TRI and Tsk7L or TSR1, we have defined the structural requirements for TGF- signaling by TRI. The extracellular/transmembrane or cytoplasmic domains of TRI and Tsk7L were functionally not equivalent. The juxtamembrane domain, including the GS motif, and most regions in the kinase domain can functionally substitute for each other, but the C–4–5 region from kinase subdomains III to V conferred a distinct signaling ability. Replacement of this sequence in TRI by the corresponding domain of Tsk7L inactivated TGF- signaling, whereas its introduction into Tsk7L conferred TGF- signaling. The differential signaling associated with this region was narrowed down to a sequence of eight amino acids, the L45 loop, which is exposed in the three-dimensional kinase structure and diverges highly between TRI and Tsk7L or TSR1. Replacement of the L45 sequence in Tsk7L with that of TRI conferred TGF- responsiveness to the Tsk7L cytoplasmic domain in Mv1Lu cells. Thus, the L45 sequence between kinase subdomains IV and V specifies TGF- responsiveness of the type I receptor.