The K650E substitution in the fibroblast growth factor receptor 3 (FGFR3) causes constitutive tyrosine kinase activity of the receptor and is associated to the lethal skeletal disorder, thanatophoric dysplasia type II (TDII). The underlying mechanisms of how the activated FGFR3 causes TDII remains to be elucidated. FGFR3 is a transmembrane glycoprotein, which is synthesized through three isoforms, with various degrees of N-glycosylation. We have studied whether immature FGFR3 isoforms mediate the abnormal signaling in TDII. We show that synthesis of TDII-FGFR3 presents two phosphorylated forms: the immature non-glycosylated 98-kDa peptides and the intermediate 120-kDa glycomers. The mature, fully glycosylated 130-kDa forms, detected in wild type FGFR3, are not present in TDII. Endoglycosidase H cleaves the sugars on TDII intermediates thus indicating their intracellular localization in the endoplasmic reticulum. Accordingly, TDII-FGFR3-GFP co-localizes with calreticulin in the endoplasmic reticulum. Furthermore, following TDII transfection, signal transducer and activator of transcription 1 (STAT1) is phosphorylated in the absence of FGFR3 ligand and brefeldin A does not inhibit its activation. On the contrary, the cell membrane-anchored FRS2alpha protein is not activated in TDII cells. The opposite situation is observed in stable TDII cell clones where, despite the presence of phosphorylated mature receptor, STAT1 is not activated whereas FRS2alpha is phosphorylated. We speculate that the selection process favors cells defective in STAT1 activation through the 120-kDa TDII-FGFR3, thus allowing growth of the TDII cell clones. Accordingly, apoptosis is observed following TDII-FGFR3 transfection. These observations highlight the importance of the immature TDII-FGFR3 proteins as mediators of an abnormal signaling in TDII.