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Novel non-TGF-ß-binding splice variant of LTBP-4 in human cells and tissues provides means to decrease TGF-ß deposition

Departments of Virology and Pathology, the Haartman Institute and Biomedicum Helsinki, University of Helsinki and Helsinki University Hospital, FIN-00014 Helsinki, Finland
^* Author for correspondence (e-mail: katri.koli{at}helsinki.fi

Accepted April 23, 2001

Small latent TGF-ß consists of latency associated peptide (LAP) bound to the 25 kDa TGF-ß by noncovalent interactions. Small latent TGF-ß is secreted from cells and deposited into the extracellular matrix as covalent complexes with its binding proteins, LTBPs. Four LTBPs have been molecularly cloned and their structures contain repetitive sequences. The 3^rd 8-Cys repeats of LTBP-1, -3 and -4 are able to associate with small latent TGF-ß. We analyzed by RT-PCR the expression of LTBPs 1-4 in a panel of cultured human cell lines including fibroblasts of different origin, endothelial cells and immortalized keratinocytes. LTBPs were expressed in an overlapping manner, but differences in their expression levels were detected. SV-40 transformed human embryonic lung fibroblasts contained less of the mRNAs for the LTBPs, suggesting that malignant transformation leads to decrease in LTBP expression. A novel alternatively spliced form of LTBP-4 lacking the 3^rd 8-Cys repeat (LTBP-48-Cys^3rd) was identified. LTBP-48-Cys^3rd does not bind TGF-ß and it was found to be expressed in the same tissues as the full length LTBP-4. The exon-intron structure of LTBP-4 around the 3^rd 8-Cys repeat was similar to those of LTBP-2 and -3. LTBP-48-Cys^3rd was produced by alternative splicing over two exons. In addition, HL-60 promyelocytic leukemia cells expressed a splice variant lacking only one exon of this region. The expression of the non-TGF-ß-binding variant of LTBP-4 may be important for the regulation of TGF-ß deposition in tissues. Since LTBPs are a part of the extracellular matrix microfibrils, the LTBP-48-Cys^3rd protein may also be involved in various structural functions not related to TGF-ß signaling.

Key words: LTBP, TGF-ß, 8-Cys repeat, Alternative splicing

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				C. Penttinen, J. Saharinen, K. Weikkolainen, M. Hyytiainen, and J. Keski-Oja Secretion of human latent TGF-{beta}-binding protein-3 (LTBP-3) is dependent on co-expression of TGF-{beta} J. Cell Sci., January 9, 2002; 115(17): 3457 - 3468. [Abstract] [Full Text] [PDF]