The Couchman laboratory is focused on how cell behavior is regulated by interactions with the extracellular matrix with which cells and tissues are in contact. The extracellular matrix, once considered inert, is now known to be a key influence on survival, proliferation, differentiation, adhesion and migration. Receptors at the cell surface are the sensors of the environment and we aim to understand how they function.
Interactions between cells and tissues and their surroundings are essential at all phases of multicellular animal development, homeostasis and tissue repair, and are often altered in disease. Our goal is to understand the functions of the cell surface receptors known as syndecans. They are implicated in a variety of diseases, including some cancers and cardiovascular disease. By dissecting their roles at a molecular level, we aim to discover new potential for intervention.
For many years it was unclear how syndecans contributed to the regulation of cell behavior. A few years ago we had a major breakthrough with the discovery that these receptors controlled cytoplasmic calcium levels through a group of channels known as TRPCs. We could demonstrate specific regulation not only by two mammalian syndecans but also the single syndecan of Caenorhabditis elegans, a powerful invertebrate genetic model. This in turn informed us that calcium regulation by syndecans is an evolutionarily conserved function. Interactions with collaborators at The University of Oslo further revealed that the syndecan-TRPC axis may be intirinsic to a common form of heart failure.
- Having established the roles of syndecan-4, we have turned to syndecan-1, whose signaling functions are unclear. This syndecan is important, since it is often upregulated in cancers, e.g. breast cancer, where its levels can be prognostic for survival. We are using a number of approaches, including gene deletions, RNAseq, bioinformatics and molecular cell biology.
- We entered the syndecan field after discovering some 30 years ago that one member, syndecan-4, has roles in promoting the formation of an organelle involved in cell adhesion and migration known as focal adhesions (or focal contacts). More recently we found not only that a TRPC channel was present, but additionally a calcium activated channel, TRPM4. Its role is not understood, and we are using a number of approaches to investigate this channel.
Transmembrane proteoglycans control stretch-activated channels to set cytosolic calcium levels. S. Gopal, P. Søgaard, H.A.B. Multhaupt, C. Pataki, E. Okina, X. Xian, M.E. Pedersen, T. Stevens, O. Griesbeck, P.W. Park, R. Pocock and J.R. Couchman. 2015. J. Cell Biol. 210: 1199-1211. PMID: 26391658
Recent insights into cell surface heparan sulphate proteoglycans and cancer. J.R. Couchman, H. Multhaupt and R.D. Sanderson. 2016. F1000 Faculty Rev.1541 doi: 10.12688/f1000research. 8543.1 PMID: 27408707
Cell-extracellular matrix and cell-cell adhesion are linked by syndecan-4. S. Gopal, H.A. Multhaupt, R. Pocock and J.R. Couchman. 2017. Matrix Biol. 60-61:57-69. PMID: 27751945
Proteoglycans, ion channels and cell-matrix adhesion. I. Mitsou, H.A. Multhaupt and J.R. Couchman. 2017. Biochem. J. 474: 1965-79. PMID: 28546458
Calcium in cell-extracellular matrix interactions. S. Gopal, H.A.B. Multhaupt and J.R. Couchman. 2020. Adv. Exp. Med. Biol. 1131:1079-1102. PMID: 31646546