CRITICAL CYTOPLASMIC DOMAINS OF HUMAN INTERLEUKIN-9 RECEPTOR-ALPHA CHAIN IN INTERLEUKIN-9-MEDIATED CELL-PROLIFERATION AND SIGNAL-TRANSDUCTION

Interleukin-9 receptor (IL-9R) complex consists of a ligand specific a u chain and IL-2R gamma chain, In this study, two regions in the cytop lasmic domain of human IL-9R alpha were found to be important for IL-9 -mediated cell growth. A membrane-proximal region that contains the BO X1 consensus sequence is required for IL-9-induced cell proliferation and tyrosine phosphorylation of Janus kinases (JAKs), Deletion of this region or internal deletion of the BOX1 motif abrogated IL-9-induced cell proliferation and signal transduction. However, substitution of t he Pro-X-Pro in the BOX1 motif with Ala-X-Ala failed to abolish IL-9-i nduced cell proliferation but decreased IL-g-mediated tyrosine phospho rylation of JAM kinases, insulin receptor substrate-2, and signal tran sducer and activator of transcription 3 (STAT3) and expression of c-my c and junB. Another important region is downstream of the BOX1 motif a nd contains a STAT3 binding motif YLPQ. Deletion of this region signif icantly impaired IL-9-induced cell growth, activation of JAK kinases, insulin receptor substrate-g, and STAT3 and expression of early respon se genes, A point mutation changing YLPQ into YLPA ,greatly reduced IL -9-induced activation of STAT3 and expression of c-myc but did not aff ect cell proliferation, These results suggest that cooperation or cros s-talk of signaling molecules associated with different domains of IL- 9R alpha other than STAT3 is essential for IL-9-mediated cell growth.