We are interested in extracellular biology and the regulation of cell behaviour. Nearly all cells and tissues are in contact with, and adherent to, an extracellular matrix (ECM). Essential in all multicellular animals, ECM is required through development and for immune function, homeostasis, physical support and tissue repair. ECM takes many forms depending on its role, ranging from the connective tissues of skin and other organs, to skeletal structures that comprise cartilage and bone.
Importantly, many diseases of man involve ECM changes, or alterations in cellular interactions with ECM components. Examples are tumour invasion, diabetic fibrosis that leads to loss of sight or kidney function, arthritis and cardiovascular disease. It is therefore important to understand how cells respond to the molecules present in ECM, and how this regulates cell behaviour.
One important receptor that we focus on is syndecan-4, a small heparan sulphate containing proteoglycan. We have established that it works in conjunction with integrin receptors to promote junctions known as focal adhesions.
- The relevance of syndecan-4 is underscored by data showing defects in cell adhesion and migration when the gene is deleted in the mouse. Ongoing work is directed into several projects.
- Although we have established the structure of the cytoplasmic domain of syndecan-4, the extracellular domain of this receptor remains to be characterised. Work is ongoing to elucidate the structure of this part of syndecan-4.
- Detailed analysis of the carbohydrate chains (heparan sulphate) is underway to determine how binding of ligands can lead to signaling responses inside the cell.
- The molecular linkages between syndecan-4 and the actin cytoskeleton are not well understood, and a variety of cellular, molecular and structural work is in progress. Of particular interest is an interaction between syndecan-4 and the actin-bundling protein α-actinin.
- Extensive studies of syndecan-4 and its relatives in cancer are underway. Evidence suggests potential roles in the tumour stroma that may be important in tumour progression. This is consistent with known abilities of syndecan-4 to promote adhesion leading to ECM contraction. The hypothesis that syndecan-4 is important in the conversion of fibroblasts to myofibroblasts is being investigated.
Lendorf ME, Manon-Jensen T, Kronqvist P, Multhaupt HA, Couchman JR. Syndecan-1
and syndecan-4 are independent indicators in breast carcinoma. J Histochem
Cytochem. 2011 Jun;59(6):615-29
Manon-Jensen T, Itoh Y, Couchman JR. Proteoglycans in health and disease: the
multiple roles of syndecan shedding. FEBS J. 2010 Oct;277(19)
Whiteford JR, Xian X, Chaussade C, Vanhaesebroeck B, Nourshargh S, Couchman
JR. Syndecan-2 is a novel ligand for the protein tyrosine phosphatase receptor
CD148. Mol Biol Cell. 2011 Oct;22(19):3609-24
Ard R, Mulatz K, Abramovici H, Maillet JC, Fottinger A, Foley T, Byham MR,
Iqbal TA, Yoneda A, Couchman JR, Parks RJ, Gee SH. Diacylglycerol kinase ζ
regulates RhoA activation via a kinase-independent scaffolding mechanism. Mol
Biol Cell. 2012 Oct;23(20):4008-19
Yoneda A, Morgan-Fisher M, Wait R, Couchman JR, Wewer UM. A collapsin response
mediator protein 2 isoform controls myosin II-mediated cell migration and matrix
assembly by trapping ROCK II. Mol Cell Biol. 2012 May;32(10):1788-804
Galli GG, Honnens de Lichtenberg K, Carrara M, Hans W, Wuelling M, Mentz B,
Multhaupt HA, Fog CK, Jensen KT, Rappsilber J, Vortkamp A, Coulton L, Fuchs H,
Gailus-Durner V, Hrabě de Angelis M, Calogero RA, Couchman JR, Lund AH. Prdm5
regulates collagen gene transcription by association with RNA polymerase II in
developing bone. PLoS Genet. 2012;8(5):e1002711
Okina E, Grossi A, Gopal S, Multhaupt HA, Couchman JR. Alpha-actinin
interactions with syndecan-4 are integral to fibroblast-matrix adhesion and
regulate cytoskeletal architecture. Int J Biochem Cell Biol. 2012
Couchman JR, Pataki CA. An introduction to proteoglycans and their
localization. J Histochem Cytochem. 2012 Dec;60(12):885-97
Holmborn K, Habicher J, Kasza Z, Eriksson AS, Filipek-Gorniok B, Gopal S,
Couchman JR, Ahlberg PE, Wiweger M, Spillmann D, Kreuger J, Ledin J. On the roles
and regulation of chondroitin sulfate and heparan sulfate in zebrafish pharyngeal
cartilage morphogenesis. J Biol Chem. 2012 Sep 28;287(40):33905-16
Multhaupt HA, Couchman JR. Heparan sulfate biosynthesis: methods for
investigation of the heparanosome. J Histochem Cytochem. 2012 Dec;60(12):908-15