Abstract
Transforming growth factor (TGF)‐β is secreted and targeted into the extracellular matrix (ECM) in association with one of the latent TGF‐β binding proteins (LTBPs). Activation of these latent complexes is an important regulatory step in TGF‐β 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‐β1, 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. J. Cell. Physiol. 223:727–736, 2010. © 2010 Wiley‐Liss, Inc.