A KINASE SUBDOMAIN OF TRANSFORMING GROWTH-FACTOR-BETA (TGF-BETA) TYPE-I RECEPTOR DETERMINES THE TGF-BETA INTRACELLULAR SIGNALING SPECIFICITY

Transforming growth factor-beta (TGF-beta) signals through a heteromer ic complex of related type I and type II serine/threonine kinase recep tors. In Mv1Lu cells the type I receptor T beta R1 mediates TGF-beta-i nduced gene expression and growth inhibition, while the closely relate d type I receptors Tsk7L and TSR1 are inactive in these responses, Usi ng chimeras between T beta RI and Tsk7L or TSR1, we have defined the s tructural requirements for TGF-beta signaling by T beta RI, The extrac ellular/transmembrane or cytoplasmic domains of T beta RI and Tsk7L we re functionally not equivalent. The juxtamembrane domain, including th e GS motif, and most regions in the kinase domain can functionally sub stitute for each other, but the alpha C-beta 4-beta 5 region from kina se subdomains III to V conferred a distinct signaling ability, Replace ment of this sequence in T beta RI by the corresponding domain of Tsk7 L inactivated TGF-beta signaling, whereas its introduction into Tsk7L conferred TGF-beta signaling, The differential signaling associated wi th this region was narrowed down to a sequence of eight amino acids, t he L45 loop, which is exposed in the three-dimensional kinase structur e and diverges highly between T beta RI and Tsk7L or TSR1, Replacement of the L45 sequence in Tsk7L with that of T beta RI conferred TGF-bet a responsiveness to the Tsk7L cytoplasmic domain in Mv1Lu cells. Thus, the L45 sequence between kinase subdomains IV and V specifies TGF-bet a responsiveness of the type I receptor.