Current Projects
Hovedinnhold
Overall aim
Our group aims to understand the molecular mechanisms by which the HS elongating enzymes, the Exostosin family, influence HS structure and HS function as a cell matrix receptor and as co-receptors for signaling molecules.
The exostosin (EXT) enzymes take part in HS biosynthesis where they have a key role in generating the HS polysaccharide backbone. The human EXT-family consists of five members, EXT1, EXT2 and three EXT-Like proteins (EXTL1, EXTL2 and EXTL3). EXT1, EXT2 and EXTL3 are necessary for HS chain formation and complete loss of HS chains caused by deletion of Ext1, Ext2 or Extl3 in mouse models is incompatible with life. The functions of EXTL1- and EXTL2-proteins in HS biosynthesis are unclear. Extl2 deficient mice are fertile and have HS chains. No Extl1 deficient mouse has been reported so far. Heterozygote mutations in EXT1 or EXT2 result in the human disorder multiple osteochondromas and predispose to the development of chondrosarcoma.
We have shown that changes in the levels of the EXT-proteins are important for HS-regulated growth factor binding and signaling and for fibroblast to attach to collagen I. We recently showed that HS on fibroblasts strongly influences the behavior, migration and gene expression of tumor cells in fibroblast/tumor co-culture cell model. We have recently also performed a biochemical characterization of the EXTs and HS structure in breast carcinoma cell lines. Our study suggests that the gene expression profiles of EXTs changes in breast carcinomas. However, this is not reflected in HS structure, which has a much more complicated regulation than the regulation ofthe mRNA levels of the biosynthetic enzymes.
Projects
1. To study the molecular mechanisms by which the HS elongating enzymes, the EXT-family, influence HS structure, TGF-β1 levels and activity, and its effect on cancer cells.
2. To study the role of the EXT-family in oral cancer.
3. To study the molecular mechanisms for the action of the EXT-family of proteins for HS structure and HS function as co-receptors for signaling receptors.
Relevant References:
Busse-Wicher, M., Wicher, K.B. and Kusche-Gullberg, M. The extostosin family: Proteins with many functions. Matrix Biol 35, 25-33 (2014) review
Österholm, C., Barczyk, M.M., Busse, M., Grønning, M, Reed, R.K. and Kusche-Gullberg, M. Mutation in the heparan sulfate biosynthesis enzyme EXT influences growth factor signaling and fibroblast interactions with the extracellular matrix. J Biol Chem 284, 34935-34943 (2009)
Österholm C., Lu, N., Lidén Å., Gullberg D, Reed R.K. and Kusche-Gullberg M. Fibroblast EXT1-levels Influence Tumor Cell Proliferation and Migration in Composite Spheroids. PLoS One 7(7):e41334 (2012)
Katta, K., Sembajwe, L, F. , Kusche-Gullberg, M. Potential role for Ext1-dependent heparan sulfate inregulating P311 gene expression in A549 carcinoma cells Biochim Biophys Acta. 1862(6):1472-148, (2018)
Sembajwe LF, Katta K, Grønning M, Kusche-Gullberg M. The exostosin family of glycosyltransferases: mRNA expression profiles and heparan sulphate structure in human breast carcinoma cell lines. Biosci Rep. BSR2018077(2018)
