Independent regulation of short and long forms of latent TGF-beta binding protein (LTBP)-4 in cultured fibroblasts and human tissues.

Transforming growth factor (TGF)-beta is secreted and targeted into the extracellular matrix (ECM) in association with one of the latent TGF-beta binding proteins (LTBPs). Activation of these latent complexes is an important regulatory step in TGF-beta signaling. LTBPs target the growth factor into the ECM and expose it to activating mechanisms. Disruption of LTBP-4 gene causes severe developmental abnormalities in both humans and mice. Transcripts for two N-terminally distinct LTBP-4 variants, LTBP-4S (short) and -4L (long), have been identified. In the current work, we have characterized differences in the expression, processing, and ECM targeting of these LTBP-4 variants. Heart and skeletal muscle displayed expression of both variants, while liver expressed mainly LTBP-4L and lung as well as small intestine LTBP-4S. This tissue-specific expression pattern was found to originate from control of transcription by two independent promoters. Furthermore, LTBP-4S and -4L proteins were secreted and processed differently. During secretion, LTBP-4L was complexed with TGF-beta1, whereas the majority of LTBP-4S was secreted in a free form. In addition, LTBP-4S was incorporated into the ECM, while full-length LTBP-4L was not readily detectable in the ECM. These data suggest that LTBP-4 functions are modified by tissue-specific expression of the two N-terminally distinct variants, which in addition exhibit significant differences in cellular processing and targeting, that is, this provides a basis for understanding molecular diversity in LTBP-4 structure and function.

Kantola AK ，Ryynänen MJ ，Lhota F ，Keski-Oja J ，Koli K ... -  《-》

Sequential deposition of latent TGF-beta binding proteins (LTBPs) during formation of the extracellular matrix in human lung fibroblasts.

Koli K ，Hyytiäinen M ，Ryynänen MJ ，Keski-Oja J ... -  《EXPERIMENTAL CELL RESEARCH》

Analysis of the expression pattern of the latent transforming growth factor beta binding protein isoforms in normal and diseased human liver reveals a new splice variant missing the proteinase-sensitive hinge region.

Michel K ，Roth S ，Trautwein C ，Gong W ，Flemming P ，Gressner AM ... -  《HEPATOLOGY》

MT1-MMP releases latent TGF-beta1 from endothelial cell extracellular matrix via proteolytic processing of LTBP-1.

Tatti O ，Vehviläinen P ，Lehti K ，Keski-Oja J ... -  《-》

Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer.

Sterner-Kock A ，Thorey IS ，Koli K ，Wempe F ，Otte J ，Bangsow T ，Kuhlmeier K ，Kirchner T ，Jin S ，Keski-Oja J ，von Melchner H ... -  《GENES & DEVELOPMENT》